European Journal of Obstetrics & Gynecology and Reproductive Biology 192 (2015) 47–53
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Prescribing patterns of antenatal corticosteroids in women with threatened preterm labor Femke F. Wilms a,*, Gert-Jan van Baaren b, Jolande Y. Vis c, Martijn A. Oudijk d, Anneke Kwee d, Martina M. Porath e, Hubertina C.J. Scheepers f, Marc E.A. Spaanderman f, Kitty W.M. Bloemenkamp g, Antoinette C. Bolte h, Caroline J. Bax h, Je´roˆme M.J. Cornette i, Johannes J. Duvekot i, Bas W.A. Nij Bijvank j, Jim van Eyck j, Maureen T.M. Franssen k, Krystyna M. Sollie k, Frank P.H.A. Vandenbussche l, Mallory D. Woiski l, Joris A.M. van der Post b, Patrick M.M. Bossuyt m, Brent C. Opmeer m, Ben W.J. Mol n a
Department of Obstetrics & Gynecology, Catharina Hospital, Eindhoven, Netherlands Department of Obstetrics & Gynecology, Academic Medical Center, Amsterdam, Netherlands Department of Clinical Chemistry & Haematology, University Medical Centre Utrecht, Utrecht, Netherlands d Department of Obstetrics & Gynecology, University Medical Center Utrecht, Utrecht, Netherlands e Department of Obstetrics & Gynecology, Maxima Medical Center, Veldhoven, Netherlands f Department of Obstetrics & Gynecology, Maastricht University Medical Center, Maastricht, Netherlands g Department of Obstetrics & Gynecology, Leiden University Medical Center, Leiden, Netherlands h Department of Obstetrics & Gynecology, VU University Medical Center, Amsterdam, Netherlands i Department of Obstetrics & Gynecology, Erasmus University Medical Center, Rotterdam, Netherlands j Department of Obstetrics & Gynecology, Isala Clinics, Zwolle, Netherlands k Department of Obstetrics & Gynecology, University Medical Center Groningen, Groningen, Netherlands l Department of Obstetrics & Gynecology, Radboud University Hospital Nijmegen, Nijmegen, Netherlands m Clinical Research Unit, Academic Medical Center, Amsterdam, Netherlands n The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 March 2015 Received in revised form 27 May 2015 Accepted 3 June 2015
Objective: To assess the impact of cervical length (CL) measurement and fetal fibronectin testing (fFN) on the clinicians’ decision to prescribe antenatal corticosteroids (ACS) to women with symptoms of preterm labor. Study design: This is a secondary analysis of a prospective cohort study including women with symptoms of preterm labor and intact membranes between 24 and 34 weeks’ gestation. We compared the proportion prescribed and completed ACS courses, preterm delivery within seven days and median intervals from ACS to delivery in four groups: group 1 CL < 10 mm, group 2 CL 10–30 mm and positive fFN, group 3 CL 10–30 mm and negative fFN, group 4 CL > 30 mm. Results: ACS were prescribed to 63/65 (97%) women in group 1, 176/192 (91%) in group 2, 111/172 women (65%) in group 3 and 55/242 (23%) in group 4. In group 1, 42 (65%) women delivered within seven days, compared to 34 (18%) in group 2, 6 (3%) in group 3 and 3 (1%) in group 4. Median intervals between ACS and delivery were 6 days (IQR 3–61 days), 44 days (IQR 17–69 days), 53 days (IQR 37–77 days) and 66 days (IQR 43–78 days) in group 1, 2, 3 and 4 respectively. Conclusion: ACS were prescribed frequently to women with a CL of 10–30 mm and a negative fFN test or a CL > 30 mm. There is room for improvement in the prescription of ACS in these low risk women. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Antenatal corticosteroids Cervical length Fetal fibronectin Preterm labor
Introduction Preterm delivery (PTD) is a major contributor to neonatal morbidity and mortality [1,2]. Antenatal corticosteroids (ACS) * Corresponding author at: Department of Obstetrics and Gynecology, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, Netherlands. Tel.: +31 628154199. E-mail address: [email protected] (F.F. Wilms). http://dx.doi.org/10.1016/j.ejogrb.2015.06.008 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
improve the outcome of premature neonates born before 34 weeks of gestation [3–6]. Two decades have passed since the first publication on the reduction of the incidence of respiratory distress syndrome (RDS) by ACS before ACS were implemented following a recommendation by the National Institutes of Health (NIH) to administer ACS to all women at risk of PTD between 24 and 34 weeks’ gestation [7–9].
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Difficulty in accurate prediction of preterm delivery in the short term and a possible diminishing effect of ACS over time, with an optimal interval of 7–14 days between ACS and delivery, resulted in routinely repetition of ACS in the 1990s [10–17]. However no long-term benefit of repeat courses were found [18–24]. Furthermore a lower neonatal birth weight and smaller head circumference were reported, although the long-term outcomes at 2–3 years of age seemed to be reassuring. Nowadays a ‘‘rescue’’ course of ACS can be considered [25–27]. Optimal timing of the first course of ACS can prevent the rise of the question whether or not to repeat a course. In women with symptoms of PTL, measurement of the cervical length (CL) by vaginal ultrasound in combination with fetal fibronectin (fFN) testing might improve the recognition of women at low risk of PTD within the next seven days [28–32]. In this cohort study, we assessed clinicians’ prescribing patterns of ACS in relation to CL and fFN results in women with symptoms of PTL. We hypothesize that clinicians inadequately time treatment of women at low risk for PTD. Materials and methods This study was a secondary analysis of data collected in the APOSTEL-1 study. The APOSTEL-1 study was a prospective cohort study performed in all ten perinatal centers in The Netherlands between December 2009 and August 2012. The principal aim of the study was to access the accuracy of fFN testing and CL measurement in women with symptoms of PTL. The study protocol received IRB-approval (MEC 08/363), and methods have been reported previously [33]. Participants and interventions The APOSTEL-1 study included women with symptoms of PTL, such as contractions (>3 per 30 min), vaginal bleeding, or abdominal/back pain between 24 and 34 weeks of gestation and intact membranes. Women who received tocolytic treatment within the previous seven days were excluded, except for those who received a single dose of tocolytic treatment for transportation to a tertiary hospital. Other exclusion criteria were more than 3 cm dilatation diagnosed at digital examination and contraindications for tocolysis, such as lethal congenital abnormalities, suspected intra-uterine infection or non-reassuring fetal status. At admission a fFN test (rapid fetal fibronectin TLIIQ analyser (Hologic Benelux B.V.1 Almere, the Netherlands) with a 0.050 mg/mL cutoff) was taken from the posterior fornix, the CL was measured by transvaginal ultrasound and a digital examination was performed to assess cervical changes. No strict protocol was available for treatment decisions, but recommendations were provided. Tocolysis was recommended according to local protocol in women with a CL below 10 mm (group 1) or a CL between 10 and 30 mm and a positive fFN test (group 2). In women with a CL between 10 and 30 mm and a negative fFN test (group 3) the clinician on call decided whether to start tocolysis. We recommended to withhold tocolytic treatment in women with a CL above 30 mm (group 4). Clinicians could prescribe nifedipine, indomethacin, atosiban and/or ritodrine. Corticosteroids were given to women at the discretion of the clinician on call [32]. Outcomes and statistical analysis A complete course ACS was defined as two doses of 12 mg Celestone Chronodose (Merck Sharp & Dohme bv, Brussels, Belgium) intramuscularly with a 24-h interval. For women who received a complete, an incomplete (1 dose) or no ACS course we calculated median gestational age at delivery,
median gestational age at ACS treatment and the median interval from study enrollment to delivery, all with interquartile ranges (IQR). A Kaplan–Meier plot was derived to illustrate the interval from enrollment to preterm delivery (before 34 weeks). To evaluate the influence of a prolonged interval between a complete course ACS at enrollment and preterm delivery before 34 weeks gestation on the neonatal respiratory outcome, we compared intubation rate of neonates born alive within or beyond seven days after administration of ACS and calculated the odds ratios (OR) with 95% confidence intervals (95% CI). Since the gestational age at which neonates are born is of influence on the respiratory outcome, we evaluated the intubation rates per two weeks gestation. Among the four groups based on CL and fFN result we evaluated the proportion prescribed and the proportion completed courses of ACS at study enrollment, the PTD rates within seven days after study enrollment and before 34 weeks gestation and the interval between ACS treatment and delivery. Mode of delivery was described for the women who delivered prematurely. A Kaplan– Meier plot was made to illustrate the interval from the time from the first ACS gift of a complete course to preterm delivery (before 34 weeks). Data were censored after 28 days, since ACS are unlikely to be beneficial if delivery occurs after this period. To evaluate the prescribing patterns of ACS at study enrollment we analyzed women who received no ACS treatment at study enrollment, but were treated later on in pregnancy, as if they received no ACS treatment. To evaluate prescribing patterns during the course of pregnancy we analyzed the proportion postponed and repeated ACS courses and PTD rates after a postponed or repeated course. Finally, we assessed the following characteristics: parity, ethnicity, smoking, previous preterm delivery, singleton vs. multiple pregnancy and referral from primary care midwifery practice or secondary care center. Stratified analyses were performed since these characteristics might influence the risk assessment of PTD and therewith the prescribing patterns of ACS. Statistical analyses were performed using SPSS software, version 21.0 (SPSS Inc. Chicago, IL, USA). Results Between December 2009 and August 2012, 758 women were approached for the APOSTEL-1 study. We included 671 women in the analysis (Fig. 1). The median gestational age at study enrollment was 29.4 weeks (IQR 27–31.3). Of the included women, 324 (48%) were multiparous of whom 145 (45%) had a previous premature delivery. The cohort contained 104 (14%) multiple pregnancies. A cesarean section was performed in 144 (21%) women. Further baseline characteristics can be found in Table 1. Total population Of the 671 women with symptoms of PTL, 371 (55%) received a complete ACS course, 34 (5%) an incomplete course and 266 (40%) received no ACS treatment at enrollment (Table 2). The median interval from enrollment to delivery among women who received a complete course, an incomplete course or no ACS at study enrollment was 46 days (IQR 25–72) days, 1 day (IQR 0–3.25) and 62 days (IQR 46–80) days respectively (p < 0.001). The Kaplan–Meier curve in Fig. 2 illustrates the interval from study enrollment to delivery and PTD before 34 weeks. Out of the 100 women who completed an ACS course and delivered before 34 weeks of gestation 124 neonates were born alive. Table 3 shows the intubation rate of neonates born before 34 weeks of gestation within or beyond seven days after administration of a complete course of ACS, categorized per two weeks of gestation. No significant odds ratios were found. Virtually all neonates born
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Women eligible for study (n=758) No inclusion (n=5) No gestational age between 24-34 weeks (n=3) Ruptured membranes (n=1) No signs of preterm labor (n=1)
Women eligible for study (n=753)
Exclusion (n=23) Tocolysis for more than 12 hours (n=15) More than 3 cm dilatation (n=6) Lethal congenital abnormality (n=2) Intra-uterine infection (n=2)
No informed consent (n=16)
Women included in cohort (n=714)
Either fetal fibronectin or cervical length result not available (n=43)
Women analyzed (n=671)
CL < 10 mm (n=65)
CL 10-30 + fFN pos (n=192)
CL 10-30 + fFN neg (n=172)
CL > 30 mm (n=242)
Fig. 1. Flow diagram.
before a gestational age of 28 weeks were in need of intubation, with higher odds of intubation if neonates were born within seven days after ACS administration (GA 24–25 6/7: OR 2.33 (95% CI 0.062–87.9); GA 26–27 6/7: OR 15.00 (95% CI 0.60–376.72)). After a gestational age of 28 weeks however, neonates born within seven days after ACS administration were at lower risk of intubation compared to those born with in interval of more than seven days between ACD administration and delivery (GA 28–29 6/7: OR 0.68 (95% CI 0.12–3.82); GA 30–31 6/7: OR 0.11 (95% CI 0.012–1.04); GA 32–33 6/7: OR 0.19 (0.009–3.66)) (Table 3). Subgroups Among the four groups according to CL and fFN the proportion completed ACS courses differed significantly (p = 0.001) (Table 2). Group 1 CL < 10 mm Group 1 consisted of 65 women. The median gestational age at study enrollment was 28 1/7 weeks (IQR 26 1/7–30 2/7). The
median gestational age at delivery was 30 4/7 weeks (IQR 28 0/7– 34 1/7). ACS were prescribed to 63 women (97%) at study enrollment. Forty-two (65%) women delivered within seven days after enrollment (Table 2). To two women (3%) no ACS was prescribed, these women did not deliver within seven days and received no ACS treatment further on in pregnancy (Table 4). ACS were repeated in 6 (29%) (1 incomplete and 5 complete courses) of the 21 women who completed a course at enrollment, after which one woman (17%) delivered within the following seven days. Group 2 CL 10–30 mm and a positive fFN test Group 2 consisted of 192 women. The median gestational age of these women at study enrollment was 29 3/7 weeks (IQR 27 0/ 7–31 0/7). The median gestational age at delivery was 36 4/7 weeks (IQR 31 3/7–38 2/7). ACS were prescribed to 176 women (91%). PTD within seven days occurred in 34 (18%) women (Table 2). Three (19%) of the 16 women to whom initially no ACS were prescribed received ACS further on in pregnancy, one (33%) of them delivered within seven days after treatment. One woman
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Table 1 Baseline characteristics. n = 671 Nulliparous Maternal age (years) Gestational age at study enrollment (weeks) Caucasian ethnicity Maternal smokinga (n = 625) Body-mass indexa (first antenatal visit, kg/m2) Previous preterm delivery Singleton Twin Triplet Referral from peripheral hospital or midwife Fetal fibronectin Positive Negative Digital examinationa (n = 624) Cervical dilation < 3 cm Mode of delivery Spontaneously Assisted vaginaly Cesarean section
347 (51.7%) 29.2 (5.3) 29.4 (IQR 27–31.3) 448 (66.8%) 90 (14.4%) 22.3 (IQR 20.3–25.1) 145 (21.6%) 567 (84.5%) 102 (14.1%) 2 (0.3%) 425 (63%) 306 (45.6%) 365 (54.4%) 606 (97.1%) 464 (69%) 63 (10%) 144 (21%)
Fig. 2. Kaplan–Meier curves illustrating the time from study enrollment to preterm delivery before 34 weeks of gestation, censored after 28 days.
Data are number of patients (%), mean (SD) or median (IQR). a Data are missing for some participants.
delivered before a gestational age of 34 weeks without treatment with ACS (Table 4). ACS were repeated in 15 (11%) (3 incomplete and 12 complete courses) of the 139 women who received a complete course at enrollment, after which six (40%) women delivered within seven days. Group 3 CL 10–30 mm and a negative fFN test Group 3 consisted of 108 women. The median gestational age of these women at study enrollment was 29 6/7 weeks (IQR 26 6/
7–31 5/7). The median gestational age at delivery was 37 6/7 weeks (IQR 36 1/7–39 5/7). ACS were prescribed to 111 (65%) women. Six (3%) women delivered within seven days after study enrollment (Table 2). Fifteen (24%) of the 61 women to whom initially no ACS were prescribed received a complete course further on in pregnancy, 2 (13%) of them delivered within seven days after treatment (Table 4). ACS ware repeated in 11 (10%) (5 incomplete and 6 complete) of the 105 women who received a complete course at enrollment, after which three (27%) women delivered within seven days.
Table 2 Completion of ACS courses at study enrollment, preterm delivery rates and mode of delivery according to CL and fFN.
No ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Incomplete course ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Complete course ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Total PTD < 7 days Mode of delivery Spontaneously Assisted Cesarean section PTD < 34 weeks Mode of delivery Spontaneously Assisted Cesarean section
Total (n = 671) N (%) Median (IQR, days)
CL < 10 mm (n = 65) N (%) Median (IQR, days)
266 2 12 62
2 0 0 75
(40%) (1%) (5%) (46–80)
(3%) (0%) (0%) (58–91)
34 (5%)
18 (28%)
28 (82%) 28 (82%) 1 (0–3.25)
18 (100%) 18 (100%) 0.5 (0–1.3)
CL 10–30 mm + fFN pos (n = 192) N (%) Median (IQR, days) 16 0 1 63
(8%) (0%) (6%) (38–79)
10 (5%) 7 (70%) 7 (70%) 1 (0–36)
371 (51%)
45 (69%)
55 (15%) 100 (27%) 46 (25–72)
24 (53%) 29 (64%) 6 (3–61)
27 (16%) 48 (29%) 44 (17–69)
85 (13%)
42 (65%)
34 (18%)
33 4 5 47
23 2 9 56
62 7 16 140
(73%) (8%) (19%) (21%)
92 (66%) 9 (6%) 39 (28%)
(78%) (10%) (12%) (72%)
36 (77%) 4 (8%) 7 (15%)
ACS, antenatal corticosteroids; CL, cervical length; fFN, fetal fibronectin; PTD, preterm delivery.
166 (86%)
(68%) (6%) (26%) (29%)
34 (61%) 4 (7%) 18 (32%)
CL 10–30 mm + fFN neg (n = 172) N (%) Median (IQR, days) 61 1 7 62
(35%) (2%) (11%) (39–80)
3 (2%) 2 (67%) 2 (67%) 1 (0.5–19) 108 (63%) 3 (3%) 14 (13%) 53 (37–77)
6 (3%) 5 0 1 23
(83%) (0%) (17%) (13%)
15 (65%) 0 (0%) 8 (35%)
CL > 30 mm (n = 242) N (%) Median (IQR, days) 187 1 4 62
(77%) (0.5%) (2%) (48–80)
3 (2%) 1 (33%) 1 (33%) 68 (1–95) 52 (21%) 1 (2%) 9 (17%) 66 (43–78)
3 (1%) 1 1 1 14
(33.3%) (33.3%) (33.3%) (6%)
7 (50%) 1 (7%) 6 (43%)
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Table 3 Neonatal respiratory outcome (intubation) in relation to the ACS-delivery-interval, gestational age at delivery categorized per 2 weeks. Total
Interval ACS to delivery 30 mm (N = 187) N (%)
237 0 2 3 3 2 26 4 8
2 0 0 0
13 0 1 1 1 0 2 0 0
46 0 0 0
176 0 1 2 2 2 9 2 1
(89%) (0%) (1%) (1%) (100%) (66%) (10%) (15%) (31%)
(100%) (0%) (0%) (0%)
0 (0%)
(81%) (0%) (8%) (6%) (100%) (0%) (13%) (0%) (0%)
(75%) (0%) (0%) (0%)
15 (25%) 2 (13%) 7 (47%)
(94%) (0%) (0.6%) (1%) (100%) (100%) (5%) (22%) (11%)
ACS, antenatal corticosteroids; CL, cervical length; fFN, fetal fibronectin; neg, negative; pos, positive; PTD, preterm delivery.
Group 4 CL > 30 mm Group 4 consisted of 242 women. The median gestational age of these women at study enrollment was 29 4/7 weeks (IQR 27 1/7– 31 1/7). The median gestational age at delivery was 38 4/7 weeks (IQR 37 3/7–40 0/7). ACS were prescribed to 55 (23%) women. Three (1%) women delivered within seven days after study enrollment (Table 2). Eleven (6%) of the 187 women to whom initially no ACS were prescribed received ACS treatment further on in pregnancy, 4 (36%) of them delivered within seven days after treatment. One (0.6%) of the 176 women who received no ACS at all, delivered before a gestational age of 34 weeks (Table 4). ACS were repeated in 4 (8%) (1 incomplete and 3 complete courses) of the 51 women who received a complete course at enrollment, after which two (50%) delivered within seven days. Median intervals between study enrollment and delivery of the women in group 1, 2, 3 and 4 who received a complete course were six days (IQR 3–61), 44 days (IQR 17–69), 53 days (IQR 37–77) and 66 days (IQR 43–78) respectively. Table 2 shows these median intervals for the women who received an incomplete course or no ACS. Cesarean section in group 1, 2, 3, and 4 was performed in 13 (20%), 43 (23%), 32 (19%) and 56 (23%) women respectively. The mode of delivery of de women in the 4 subgroups who delivered
Fig. 3. Kaplan–Meier curves illustrating the time from the first ACS administration to preterm delivery before 34 weeks of gestation, grouped by cervical length and fetal fibronectin result, censored after 28 days.
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Table 5 Completion of ACS courses at study enrollment in relation to maternal baseline characteristics. Maternal characteristics
Nulliparous Multiparous Caucasian Non-Caucasian Smoking No Stopped Yes Missing Previous PTD Yes No Singleton Multiple Referral Yes No
Total
No ACS N (%)
Incomplete ACS course N (%)
Complete ACS course N (%)
p-Valuea
Women with completed ACS course
PTD < 7 days N (%)
p-Valuea
Days between ACS and delivery Median (IQR)
p-Valuea
41 14 36 19
(19%) (11%) (14%) (16%)
0.005
45 54 46 51
(17–73) (29–75) (26–72) (23–72)
0.04
347 324 448 223
112 154 166 100
(33%) (48%) (37%) (45%)
22 12 27 7
(6%) (4%) (6%) (3%)
213 158 255 116
(61%) (48%) (57%) (52%)
30 mm. In case of recurrent or persisting threat of PTD,
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reassessment by measuring the CL and testing fFN might be considered and treatment with ACS should be reconsidered. In conclusion, this study shows that there is room for improvement in the prescribing patterns of ACS to women with symptoms of PTL but at low risk of delivery within seven days (CL of 10–30 mm and a negative fFN test or a CL > 30 mm). The interval between ACS prescription and delivery by far exceeded the recommended maximum of seven days. Better timing might result in better therapeutic results, avoiding the question whether or not to repeat ACS and prevents overtreatment and therewith lower health care costs. Consensus about ACS administration is needed and a fixed treatment protocol based on the CL and fFN results could help clinicians make their decisions when confronted with women with PTL. Funding None declared. Conflict of interest The authors report no conflict of interest. References [1] National Institutes of Health Consensus Development Conference Statement. Effect of corticosteroids for fetal maturation on perinatal outcomes. J Am Med Assoc 1995;273:413–8. [2] Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360(9344):1489–97. [3] Bonanno C, Wapner RJ. Antenatal corticosteroid treatment: what’s happened since Drs Liggins and Howie? Am J Obstet Gynecol 2009;200(April (4)):448–57. [4] Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97(1):11–25. [5] Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972–1994. Am J Obstet Gynecol 1995;175:322–35. [6] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(July (3)):CD004454. [7] 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. [8] Leviton LC, Baker S, Hassol A, Goldenberg RL. An exploration of opinion and practice patterns affecting low use of antenatal corticosteroids. Am J Obstet Gynecol 1995;173:312–6. [9] NIH Consensus Development Panel. Effect of corticosteroids for fetal maturation on perinatal outcome. J Am Med Assoc 1995;273:413–8. [10] Vermillion ST, Soper DE, Newman RB. Is betamethasone effective longer than 7 days after treatment? Obstet Gynecol 2001;97:491–3. [11] Peaceman AM, Bajaj K, Kumar P, Grobman WA. The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes. Am J Obstet Gynecol 2005;193:1165–9. [12] Sehdev HM, Abbasi S, Robertson P, et al. The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants. Am J Obstet Gynecol 2004;191:1409–13. [13] 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–.e6. [14] Wilms FF, Vis JY, Pattinaja DAPM, et al. Relationship between the time interval from antenatal corticosteroid administration until preterm birth and the occurrence of respiratory morbidity. Am J Obstet Gynecol 2011;205:49.e1–e7. [15] Planer B. Antenatal corticosteroid (ANCS) use in preterm labor in the USA. Pediatr Res 1996;39:110A. [16] Quinlivan JA, Evans SF, Dunlop SA, Beazley LD, Newnham JP. Use of corticosteroids by Australian obstetricians—a survey of clinical practice. Aust N Z J Obstet Gynaecol 1998;38:1–7. [17] Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK. BJOG 1999;106:977–9. [18] NIH Consensus Development Conference Statement. Antenatal corticosteroids revisited: repeat courses. Obstet Gynecol 2001;98:144–50. [19] Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367:1913–9.
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[39] Plaut MM, Smith W, Kennedy K. Fetal fibronectin: the impact of a rapid test on the treatment of women with preterm labor symptoms. Am J Obstet Gynecol 2003;188(6):1588–93. [40] Vis JY, Wilms FF, Oudijk MA, et al. Why were the results of randomized trials on the clinical utility of fetal fibronectin negative? A systematic review of their study designs. Am J Perinatol 2011;28(February (2)):145–50. http:// dx.doi.org/10.1055/s-0030-1263297 [Epub 2010 August 12, Review]. [41] Dutta D, Norman JE. The efficacy of fetal fibronectin testing in minimising hospital admissions, length of hospital stay and cost savings in women presenting with symptoms of pre-term labour. J Obstet Gynaecol 2010;30(November (8)):768–73. [42] Defranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013;208:233.e1–.e6. [43] van Baaren G-J, Vis JY, Grobman WA, et al. Cost-effectiveness analysis of cervical length measurement and fibronectin testing in women with threatened preterm labor. Am J Obstet Gynecol 2013;209:436.e1–.e8. [44] Lucovnik M, Chambliss LR, Garfield RE. Costs of unnecessary admissions and treatments for ‘‘threatened preterm labor’’. Am J Obstet Gynecol 2013;209: 217.e1–.e3.
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Prescribing patterns of antenatal corticosteroids in women with threatened preterm labor Femke F. Wilms a,*, Gert-Jan van Baaren b, Jolande Y. Vis c, Martijn A. Oudijk d, Anneke Kwee d, Martina M. Porath e, Hubertina C.J. Scheepers f, Marc E.A. Spaanderman f, Kitty W.M. Bloemenkamp g, Antoinette C. Bolte h, Caroline J. Bax h, Je´roˆme M.J. Cornette i, Johannes J. Duvekot i, Bas W.A. Nij Bijvank j, Jim van Eyck j, Maureen T.M. Franssen k, Krystyna M. Sollie k, Frank P.H.A. Vandenbussche l, Mallory D. Woiski l, Joris A.M. van der Post b, Patrick M.M. Bossuyt m, Brent C. Opmeer m, Ben W.J. Mol n a
Department of Obstetrics & Gynecology, Catharina Hospital, Eindhoven, Netherlands Department of Obstetrics & Gynecology, Academic Medical Center, Amsterdam, Netherlands Department of Clinical Chemistry & Haematology, University Medical Centre Utrecht, Utrecht, Netherlands d Department of Obstetrics & Gynecology, University Medical Center Utrecht, Utrecht, Netherlands e Department of Obstetrics & Gynecology, Maxima Medical Center, Veldhoven, Netherlands f Department of Obstetrics & Gynecology, Maastricht University Medical Center, Maastricht, Netherlands g Department of Obstetrics & Gynecology, Leiden University Medical Center, Leiden, Netherlands h Department of Obstetrics & Gynecology, VU University Medical Center, Amsterdam, Netherlands i Department of Obstetrics & Gynecology, Erasmus University Medical Center, Rotterdam, Netherlands j Department of Obstetrics & Gynecology, Isala Clinics, Zwolle, Netherlands k Department of Obstetrics & Gynecology, University Medical Center Groningen, Groningen, Netherlands l Department of Obstetrics & Gynecology, Radboud University Hospital Nijmegen, Nijmegen, Netherlands m Clinical Research Unit, Academic Medical Center, Amsterdam, Netherlands n The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 March 2015 Received in revised form 27 May 2015 Accepted 3 June 2015
Objective: To assess the impact of cervical length (CL) measurement and fetal fibronectin testing (fFN) on the clinicians’ decision to prescribe antenatal corticosteroids (ACS) to women with symptoms of preterm labor. Study design: This is a secondary analysis of a prospective cohort study including women with symptoms of preterm labor and intact membranes between 24 and 34 weeks’ gestation. We compared the proportion prescribed and completed ACS courses, preterm delivery within seven days and median intervals from ACS to delivery in four groups: group 1 CL < 10 mm, group 2 CL 10–30 mm and positive fFN, group 3 CL 10–30 mm and negative fFN, group 4 CL > 30 mm. Results: ACS were prescribed to 63/65 (97%) women in group 1, 176/192 (91%) in group 2, 111/172 women (65%) in group 3 and 55/242 (23%) in group 4. In group 1, 42 (65%) women delivered within seven days, compared to 34 (18%) in group 2, 6 (3%) in group 3 and 3 (1%) in group 4. Median intervals between ACS and delivery were 6 days (IQR 3–61 days), 44 days (IQR 17–69 days), 53 days (IQR 37–77 days) and 66 days (IQR 43–78 days) in group 1, 2, 3 and 4 respectively. Conclusion: ACS were prescribed frequently to women with a CL of 10–30 mm and a negative fFN test or a CL > 30 mm. There is room for improvement in the prescription of ACS in these low risk women. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Antenatal corticosteroids Cervical length Fetal fibronectin Preterm labor
Introduction Preterm delivery (PTD) is a major contributor to neonatal morbidity and mortality [1,2]. Antenatal corticosteroids (ACS) * Corresponding author at: Department of Obstetrics and Gynecology, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, Netherlands. Tel.: +31 628154199. E-mail address: [email protected] (F.F. Wilms). http://dx.doi.org/10.1016/j.ejogrb.2015.06.008 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
improve the outcome of premature neonates born before 34 weeks of gestation [3–6]. Two decades have passed since the first publication on the reduction of the incidence of respiratory distress syndrome (RDS) by ACS before ACS were implemented following a recommendation by the National Institutes of Health (NIH) to administer ACS to all women at risk of PTD between 24 and 34 weeks’ gestation [7–9].
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Difficulty in accurate prediction of preterm delivery in the short term and a possible diminishing effect of ACS over time, with an optimal interval of 7–14 days between ACS and delivery, resulted in routinely repetition of ACS in the 1990s [10–17]. However no long-term benefit of repeat courses were found [18–24]. Furthermore a lower neonatal birth weight and smaller head circumference were reported, although the long-term outcomes at 2–3 years of age seemed to be reassuring. Nowadays a ‘‘rescue’’ course of ACS can be considered [25–27]. Optimal timing of the first course of ACS can prevent the rise of the question whether or not to repeat a course. In women with symptoms of PTL, measurement of the cervical length (CL) by vaginal ultrasound in combination with fetal fibronectin (fFN) testing might improve the recognition of women at low risk of PTD within the next seven days [28–32]. In this cohort study, we assessed clinicians’ prescribing patterns of ACS in relation to CL and fFN results in women with symptoms of PTL. We hypothesize that clinicians inadequately time treatment of women at low risk for PTD. Materials and methods This study was a secondary analysis of data collected in the APOSTEL-1 study. The APOSTEL-1 study was a prospective cohort study performed in all ten perinatal centers in The Netherlands between December 2009 and August 2012. The principal aim of the study was to access the accuracy of fFN testing and CL measurement in women with symptoms of PTL. The study protocol received IRB-approval (MEC 08/363), and methods have been reported previously [33]. Participants and interventions The APOSTEL-1 study included women with symptoms of PTL, such as contractions (>3 per 30 min), vaginal bleeding, or abdominal/back pain between 24 and 34 weeks of gestation and intact membranes. Women who received tocolytic treatment within the previous seven days were excluded, except for those who received a single dose of tocolytic treatment for transportation to a tertiary hospital. Other exclusion criteria were more than 3 cm dilatation diagnosed at digital examination and contraindications for tocolysis, such as lethal congenital abnormalities, suspected intra-uterine infection or non-reassuring fetal status. At admission a fFN test (rapid fetal fibronectin TLIIQ analyser (Hologic Benelux B.V.1 Almere, the Netherlands) with a 0.050 mg/mL cutoff) was taken from the posterior fornix, the CL was measured by transvaginal ultrasound and a digital examination was performed to assess cervical changes. No strict protocol was available for treatment decisions, but recommendations were provided. Tocolysis was recommended according to local protocol in women with a CL below 10 mm (group 1) or a CL between 10 and 30 mm and a positive fFN test (group 2). In women with a CL between 10 and 30 mm and a negative fFN test (group 3) the clinician on call decided whether to start tocolysis. We recommended to withhold tocolytic treatment in women with a CL above 30 mm (group 4). Clinicians could prescribe nifedipine, indomethacin, atosiban and/or ritodrine. Corticosteroids were given to women at the discretion of the clinician on call [32]. Outcomes and statistical analysis A complete course ACS was defined as two doses of 12 mg Celestone Chronodose (Merck Sharp & Dohme bv, Brussels, Belgium) intramuscularly with a 24-h interval. For women who received a complete, an incomplete (1 dose) or no ACS course we calculated median gestational age at delivery,
median gestational age at ACS treatment and the median interval from study enrollment to delivery, all with interquartile ranges (IQR). A Kaplan–Meier plot was derived to illustrate the interval from enrollment to preterm delivery (before 34 weeks). To evaluate the influence of a prolonged interval between a complete course ACS at enrollment and preterm delivery before 34 weeks gestation on the neonatal respiratory outcome, we compared intubation rate of neonates born alive within or beyond seven days after administration of ACS and calculated the odds ratios (OR) with 95% confidence intervals (95% CI). Since the gestational age at which neonates are born is of influence on the respiratory outcome, we evaluated the intubation rates per two weeks gestation. Among the four groups based on CL and fFN result we evaluated the proportion prescribed and the proportion completed courses of ACS at study enrollment, the PTD rates within seven days after study enrollment and before 34 weeks gestation and the interval between ACS treatment and delivery. Mode of delivery was described for the women who delivered prematurely. A Kaplan– Meier plot was made to illustrate the interval from the time from the first ACS gift of a complete course to preterm delivery (before 34 weeks). Data were censored after 28 days, since ACS are unlikely to be beneficial if delivery occurs after this period. To evaluate the prescribing patterns of ACS at study enrollment we analyzed women who received no ACS treatment at study enrollment, but were treated later on in pregnancy, as if they received no ACS treatment. To evaluate prescribing patterns during the course of pregnancy we analyzed the proportion postponed and repeated ACS courses and PTD rates after a postponed or repeated course. Finally, we assessed the following characteristics: parity, ethnicity, smoking, previous preterm delivery, singleton vs. multiple pregnancy and referral from primary care midwifery practice or secondary care center. Stratified analyses were performed since these characteristics might influence the risk assessment of PTD and therewith the prescribing patterns of ACS. Statistical analyses were performed using SPSS software, version 21.0 (SPSS Inc. Chicago, IL, USA). Results Between December 2009 and August 2012, 758 women were approached for the APOSTEL-1 study. We included 671 women in the analysis (Fig. 1). The median gestational age at study enrollment was 29.4 weeks (IQR 27–31.3). Of the included women, 324 (48%) were multiparous of whom 145 (45%) had a previous premature delivery. The cohort contained 104 (14%) multiple pregnancies. A cesarean section was performed in 144 (21%) women. Further baseline characteristics can be found in Table 1. Total population Of the 671 women with symptoms of PTL, 371 (55%) received a complete ACS course, 34 (5%) an incomplete course and 266 (40%) received no ACS treatment at enrollment (Table 2). The median interval from enrollment to delivery among women who received a complete course, an incomplete course or no ACS at study enrollment was 46 days (IQR 25–72) days, 1 day (IQR 0–3.25) and 62 days (IQR 46–80) days respectively (p < 0.001). The Kaplan–Meier curve in Fig. 2 illustrates the interval from study enrollment to delivery and PTD before 34 weeks. Out of the 100 women who completed an ACS course and delivered before 34 weeks of gestation 124 neonates were born alive. Table 3 shows the intubation rate of neonates born before 34 weeks of gestation within or beyond seven days after administration of a complete course of ACS, categorized per two weeks of gestation. No significant odds ratios were found. Virtually all neonates born
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Women eligible for study (n=758) No inclusion (n=5) No gestational age between 24-34 weeks (n=3) Ruptured membranes (n=1) No signs of preterm labor (n=1)
Women eligible for study (n=753)
Exclusion (n=23) Tocolysis for more than 12 hours (n=15) More than 3 cm dilatation (n=6) Lethal congenital abnormality (n=2) Intra-uterine infection (n=2)
No informed consent (n=16)
Women included in cohort (n=714)
Either fetal fibronectin or cervical length result not available (n=43)
Women analyzed (n=671)
CL < 10 mm (n=65)
CL 10-30 + fFN pos (n=192)
CL 10-30 + fFN neg (n=172)
CL > 30 mm (n=242)
Fig. 1. Flow diagram.
before a gestational age of 28 weeks were in need of intubation, with higher odds of intubation if neonates were born within seven days after ACS administration (GA 24–25 6/7: OR 2.33 (95% CI 0.062–87.9); GA 26–27 6/7: OR 15.00 (95% CI 0.60–376.72)). After a gestational age of 28 weeks however, neonates born within seven days after ACS administration were at lower risk of intubation compared to those born with in interval of more than seven days between ACD administration and delivery (GA 28–29 6/7: OR 0.68 (95% CI 0.12–3.82); GA 30–31 6/7: OR 0.11 (95% CI 0.012–1.04); GA 32–33 6/7: OR 0.19 (0.009–3.66)) (Table 3). Subgroups Among the four groups according to CL and fFN the proportion completed ACS courses differed significantly (p = 0.001) (Table 2). Group 1 CL < 10 mm Group 1 consisted of 65 women. The median gestational age at study enrollment was 28 1/7 weeks (IQR 26 1/7–30 2/7). The
median gestational age at delivery was 30 4/7 weeks (IQR 28 0/7– 34 1/7). ACS were prescribed to 63 women (97%) at study enrollment. Forty-two (65%) women delivered within seven days after enrollment (Table 2). To two women (3%) no ACS was prescribed, these women did not deliver within seven days and received no ACS treatment further on in pregnancy (Table 4). ACS were repeated in 6 (29%) (1 incomplete and 5 complete courses) of the 21 women who completed a course at enrollment, after which one woman (17%) delivered within the following seven days. Group 2 CL 10–30 mm and a positive fFN test Group 2 consisted of 192 women. The median gestational age of these women at study enrollment was 29 3/7 weeks (IQR 27 0/ 7–31 0/7). The median gestational age at delivery was 36 4/7 weeks (IQR 31 3/7–38 2/7). ACS were prescribed to 176 women (91%). PTD within seven days occurred in 34 (18%) women (Table 2). Three (19%) of the 16 women to whom initially no ACS were prescribed received ACS further on in pregnancy, one (33%) of them delivered within seven days after treatment. One woman
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Table 1 Baseline characteristics. n = 671 Nulliparous Maternal age (years) Gestational age at study enrollment (weeks) Caucasian ethnicity Maternal smokinga (n = 625) Body-mass indexa (first antenatal visit, kg/m2) Previous preterm delivery Singleton Twin Triplet Referral from peripheral hospital or midwife Fetal fibronectin Positive Negative Digital examinationa (n = 624) Cervical dilation < 3 cm Mode of delivery Spontaneously Assisted vaginaly Cesarean section
347 (51.7%) 29.2 (5.3) 29.4 (IQR 27–31.3) 448 (66.8%) 90 (14.4%) 22.3 (IQR 20.3–25.1) 145 (21.6%) 567 (84.5%) 102 (14.1%) 2 (0.3%) 425 (63%) 306 (45.6%) 365 (54.4%) 606 (97.1%) 464 (69%) 63 (10%) 144 (21%)
Fig. 2. Kaplan–Meier curves illustrating the time from study enrollment to preterm delivery before 34 weeks of gestation, censored after 28 days.
Data are number of patients (%), mean (SD) or median (IQR). a Data are missing for some participants.
delivered before a gestational age of 34 weeks without treatment with ACS (Table 4). ACS were repeated in 15 (11%) (3 incomplete and 12 complete courses) of the 139 women who received a complete course at enrollment, after which six (40%) women delivered within seven days. Group 3 CL 10–30 mm and a negative fFN test Group 3 consisted of 108 women. The median gestational age of these women at study enrollment was 29 6/7 weeks (IQR 26 6/
7–31 5/7). The median gestational age at delivery was 37 6/7 weeks (IQR 36 1/7–39 5/7). ACS were prescribed to 111 (65%) women. Six (3%) women delivered within seven days after study enrollment (Table 2). Fifteen (24%) of the 61 women to whom initially no ACS were prescribed received a complete course further on in pregnancy, 2 (13%) of them delivered within seven days after treatment (Table 4). ACS ware repeated in 11 (10%) (5 incomplete and 6 complete) of the 105 women who received a complete course at enrollment, after which three (27%) women delivered within seven days.
Table 2 Completion of ACS courses at study enrollment, preterm delivery rates and mode of delivery according to CL and fFN.
No ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Incomplete course ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Complete course ACS at study enrollment PTD < 7 days PTD < 34 weeks Interval between study enrollment and delivery Total PTD < 7 days Mode of delivery Spontaneously Assisted Cesarean section PTD < 34 weeks Mode of delivery Spontaneously Assisted Cesarean section
Total (n = 671) N (%) Median (IQR, days)
CL < 10 mm (n = 65) N (%) Median (IQR, days)
266 2 12 62
2 0 0 75
(40%) (1%) (5%) (46–80)
(3%) (0%) (0%) (58–91)
34 (5%)
18 (28%)
28 (82%) 28 (82%) 1 (0–3.25)
18 (100%) 18 (100%) 0.5 (0–1.3)
CL 10–30 mm + fFN pos (n = 192) N (%) Median (IQR, days) 16 0 1 63
(8%) (0%) (6%) (38–79)
10 (5%) 7 (70%) 7 (70%) 1 (0–36)
371 (51%)
45 (69%)
55 (15%) 100 (27%) 46 (25–72)
24 (53%) 29 (64%) 6 (3–61)
27 (16%) 48 (29%) 44 (17–69)
85 (13%)
42 (65%)
34 (18%)
33 4 5 47
23 2 9 56
62 7 16 140
(73%) (8%) (19%) (21%)
92 (66%) 9 (6%) 39 (28%)
(78%) (10%) (12%) (72%)
36 (77%) 4 (8%) 7 (15%)
ACS, antenatal corticosteroids; CL, cervical length; fFN, fetal fibronectin; PTD, preterm delivery.
166 (86%)
(68%) (6%) (26%) (29%)
34 (61%) 4 (7%) 18 (32%)
CL 10–30 mm + fFN neg (n = 172) N (%) Median (IQR, days) 61 1 7 62
(35%) (2%) (11%) (39–80)
3 (2%) 2 (67%) 2 (67%) 1 (0.5–19) 108 (63%) 3 (3%) 14 (13%) 53 (37–77)
6 (3%) 5 0 1 23
(83%) (0%) (17%) (13%)
15 (65%) 0 (0%) 8 (35%)
CL > 30 mm (n = 242) N (%) Median (IQR, days) 187 1 4 62
(77%) (0.5%) (2%) (48–80)
3 (2%) 1 (33%) 1 (33%) 68 (1–95) 52 (21%) 1 (2%) 9 (17%) 66 (43–78)
3 (1%) 1 1 1 14
(33.3%) (33.3%) (33.3%) (6%)
7 (50%) 1 (7%) 6 (43%)
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Table 3 Neonatal respiratory outcome (intubation) in relation to the ACS-delivery-interval, gestational age at delivery categorized per 2 weeks. Total
Interval ACS to delivery 30 mm (N = 187) N (%)
237 0 2 3 3 2 26 4 8
2 0 0 0
13 0 1 1 1 0 2 0 0
46 0 0 0
176 0 1 2 2 2 9 2 1
(89%) (0%) (1%) (1%) (100%) (66%) (10%) (15%) (31%)
(100%) (0%) (0%) (0%)
0 (0%)
(81%) (0%) (8%) (6%) (100%) (0%) (13%) (0%) (0%)
(75%) (0%) (0%) (0%)
15 (25%) 2 (13%) 7 (47%)
(94%) (0%) (0.6%) (1%) (100%) (100%) (5%) (22%) (11%)
ACS, antenatal corticosteroids; CL, cervical length; fFN, fetal fibronectin; neg, negative; pos, positive; PTD, preterm delivery.
Group 4 CL > 30 mm Group 4 consisted of 242 women. The median gestational age of these women at study enrollment was 29 4/7 weeks (IQR 27 1/7– 31 1/7). The median gestational age at delivery was 38 4/7 weeks (IQR 37 3/7–40 0/7). ACS were prescribed to 55 (23%) women. Three (1%) women delivered within seven days after study enrollment (Table 2). Eleven (6%) of the 187 women to whom initially no ACS were prescribed received ACS treatment further on in pregnancy, 4 (36%) of them delivered within seven days after treatment. One (0.6%) of the 176 women who received no ACS at all, delivered before a gestational age of 34 weeks (Table 4). ACS were repeated in 4 (8%) (1 incomplete and 3 complete courses) of the 51 women who received a complete course at enrollment, after which two (50%) delivered within seven days. Median intervals between study enrollment and delivery of the women in group 1, 2, 3 and 4 who received a complete course were six days (IQR 3–61), 44 days (IQR 17–69), 53 days (IQR 37–77) and 66 days (IQR 43–78) respectively. Table 2 shows these median intervals for the women who received an incomplete course or no ACS. Cesarean section in group 1, 2, 3, and 4 was performed in 13 (20%), 43 (23%), 32 (19%) and 56 (23%) women respectively. The mode of delivery of de women in the 4 subgroups who delivered
Fig. 3. Kaplan–Meier curves illustrating the time from the first ACS administration to preterm delivery before 34 weeks of gestation, grouped by cervical length and fetal fibronectin result, censored after 28 days.
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Table 5 Completion of ACS courses at study enrollment in relation to maternal baseline characteristics. Maternal characteristics
Nulliparous Multiparous Caucasian Non-Caucasian Smoking No Stopped Yes Missing Previous PTD Yes No Singleton Multiple Referral Yes No
Total
No ACS N (%)
Incomplete ACS course N (%)
Complete ACS course N (%)
p-Valuea
Women with completed ACS course
PTD < 7 days N (%)
p-Valuea
Days between ACS and delivery Median (IQR)
p-Valuea
41 14 36 19
(19%) (11%) (14%) (16%)
0.005
45 54 46 51
(17–73) (29–75) (26–72) (23–72)
0.04
347 324 448 223
112 154 166 100
(33%) (48%) (37%) (45%)
22 12 27 7
(6%) (4%) (6%) (3%)
213 158 255 116
(61%) (48%) (57%) (52%)
30 mm. In case of recurrent or persisting threat of PTD,
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reassessment by measuring the CL and testing fFN might be considered and treatment with ACS should be reconsidered. In conclusion, this study shows that there is room for improvement in the prescribing patterns of ACS to women with symptoms of PTL but at low risk of delivery within seven days (CL of 10–30 mm and a negative fFN test or a CL > 30 mm). The interval between ACS prescription and delivery by far exceeded the recommended maximum of seven days. Better timing might result in better therapeutic results, avoiding the question whether or not to repeat ACS and prevents overtreatment and therewith lower health care costs. Consensus about ACS administration is needed and a fixed treatment protocol based on the CL and fFN results could help clinicians make their decisions when confronted with women with PTL. Funding None declared. Conflict of interest The authors report no conflict of interest. References [1] National Institutes of Health Consensus Development Conference Statement. Effect of corticosteroids for fetal maturation on perinatal outcomes. J Am Med Assoc 1995;273:413–8. [2] Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360(9344):1489–97. [3] Bonanno C, Wapner RJ. Antenatal corticosteroid treatment: what’s happened since Drs Liggins and Howie? Am J Obstet Gynecol 2009;200(April (4)):448–57. [4] Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97(1):11–25. [5] Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972–1994. Am J Obstet Gynecol 1995;175:322–35. [6] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(July (3)):CD004454. [7] 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. [8] Leviton LC, Baker S, Hassol A, Goldenberg RL. An exploration of opinion and practice patterns affecting low use of antenatal corticosteroids. Am J Obstet Gynecol 1995;173:312–6. [9] NIH Consensus Development Panel. Effect of corticosteroids for fetal maturation on perinatal outcome. J Am Med Assoc 1995;273:413–8. [10] Vermillion ST, Soper DE, Newman RB. Is betamethasone effective longer than 7 days after treatment? Obstet Gynecol 2001;97:491–3. [11] Peaceman AM, Bajaj K, Kumar P, Grobman WA. The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes. Am J Obstet Gynecol 2005;193:1165–9. [12] Sehdev HM, Abbasi S, Robertson P, et al. The effects of the time interval from antenatal corticosteroid exposure to delivery on neonatal outcome of very low birth weight infants. Am J Obstet Gynecol 2004;191:1409–13. [13] 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–.e6. [14] Wilms FF, Vis JY, Pattinaja DAPM, et al. Relationship between the time interval from antenatal corticosteroid administration until preterm birth and the occurrence of respiratory morbidity. Am J Obstet Gynecol 2011;205:49.e1–e7. [15] Planer B. Antenatal corticosteroid (ANCS) use in preterm labor in the USA. Pediatr Res 1996;39:110A. [16] Quinlivan JA, Evans SF, Dunlop SA, Beazley LD, Newnham JP. Use of corticosteroids by Australian obstetricians—a survey of clinical practice. Aust N Z J Obstet Gynaecol 1998;38:1–7. [17] Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK. BJOG 1999;106:977–9. [18] NIH Consensus Development Conference Statement. Antenatal corticosteroids revisited: repeat courses. Obstet Gynecol 2001;98:144–50. [19] Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367:1913–9.
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