Assessment of Perinatal Outcomewith Sustained Tocolysis
in Early Labor
APOSTEL-II trialDutch trial register: NTR 1336
Carolien Roos, MD, PhD student, UMC St Radboud
Dutch APOSTEL-II Collaborative Trial Group
Marc EA Spaanderman, Liesbeth HCJ Scheepers, Kitty WM Bloemenkamp, Annemiek Bolte, Jerome J Cornette, Johannes J Duvekot, Jim van
Eyck, Joke H Kok, Anneke Kwee, Ashley Merién, Brent C Opmeer, Martijn A Oudijk, Mariëlle G van Pampus, Dimitri NM Papatsonis, Martina M Porath, Sicco A Scherjon, Ewoud Schuit, Krystyne Sollie, Sylvia MC Vijgen, Christine Willekes,
Ben WJ Mol, Joris AM van der Post, Fred K Lotgering
Background
Preterm birth
75% of perinatal deaths1
High immediate and long-term costs2
Corticosteroids 48 hours prior to birth
improve neonatal outcome
Effect of sustained tocolysis has not
been proven3
1 Ananth et al. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 20062 Gilbert et al. The cost of prematurity: quantification by gestational age and birth weight. Obstet Gynecol 2003 3 Gaunekar NN, et al. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2004; CD 004071
Hypothesis
Sustained tocolysis with
nifedipine
reduces perinatal mortality and
severe perinatal morbidity
Inclusion criteria
Diagnosis of threatened preterm
labor
Gestational age: 26 to 32+2 weeks
Corticosteroids and tocolytic
treatment for 48 hours
Exclusion criteria
Pre-eclampsia or HELLP syndrome
Intrauterine infection / fetal
distress
Lethal congenital anomalies
Maternal hypertension
Placenta previa
Intervention
12 days sustained tocolysis:
Nifedipine 4 dd 20 mg orally
Placebo
Randomization
Nifedipine 4dd 20 mg orally
Placebo
t=-2 t=0 t=12
48 hrs tocolysis &
corticosteroids
Methods
Primary outcome
Composite adverse perinatal outcome
Perinatal death Chronic lung disease Intraventricular hemorrhage > grade II Periventricular leucomalacia > grade I Necrotizing enterocolitis Proven neonatal sepsis
Secondary outcomes
Gestational age at delivery Birth weight Ventilation support (days) NICU admission (days) Hospital admission (days)
Statistics
To detect a reduction of 11% in
adverse perinatal outcome,
we needed to enroll 406 patients
Intention-to-treat analysis
RR and HR; 95% CI
Kaplan-Meier curve
Eligible (n=636)
Non-randomization (n=230)
Nifedipine (n=201)
Placebo (n=205)
Allocation
Analysis
Randomized (n=406)
Exclusion
Analyzed (n=205)
Analyzed (n=201)
Baseline characteristics at randomizationRandomization
n=406Non-
randomization n=230
Nifedipinen=201
Placebon=205
Age – yrs 30.2 ± 5.1 30.2 ± 5.1
Body Mass Index # 23.3 ± 4.7 23.2 ± 4.0
Caucasian – no. (%) 166 (83) 155 (76)
Nulliparous – no.(%) 116 (58) 106 (52)
Previous preterm birth – no. (%)
39 (19) 55 (27)
Gestational age – wks 29.2 ± 1.7 29.2 ± 1.7
Multifetal gestation – no. (%)
42 (21) 48 (23)
PPROM – no. (%) 53 (26) 48 (23)
Vaginal bleeding – no. (%) 38 (19) 38 (19)
Vaginal examinationDilatation (cm)
n=1340 (0 – 1)
n=1321 (0 – 2)
Cervical length (mm) 26 (15 - 35) 23 (15 - 30)
# kg/m2Data are presented as mean ± SD or median (IQR: 25th to 75th percentile)
Baseline characteristics at randomizationRandomization
n=406Non-
randomization n=230
Nifedipinen=201
Placebon=205
Age – yrs 30.2 ± 5.1 30.2 ± 5.1 28.7 ± 5.5
Body Mass Index # 23.3 ± 4.7 23.2 ± 4.0 23.5 ± 5.0
Caucasian – no. (%) 166 (83) 155 (76) 166 (72)
Nulliparous – no.(%) 116 (58) 106 (52) 134 (58)
Previous preterm birth – no. (%)
39 (19) 55 (27) 40 (17)
Gestational age – wks 29.2 ± 1.7 29.2 ± 1.7 29.2 ± 1.9
Multifetal gestation – no. (%)
42 (21) 48 (23) 45 (20)
PPROM – no. (%) 53 (26) 48 (23) 44 (19)
Vaginal bleeding – no. (%) 38 (19) 38 (19) 43 (19)
Vaginal examinationDilatation (cm)
n=1340 (0 – 1)
n=1321 (0 – 2)
n=1111 (0 – 1)
Cervical length (mm) 26 (15 - 35) 23 (15 - 30) 24 (17 - 31)
# kg/m2Data are presented as mean ± SD or median (IQR: 25th to 75th percentile)
Prolongation of pregnancy (weeks)
HR 1.1(0.86 to 1.3)
Data are presented as mean ± SD or median (IQR: 25th to 75th percentile)
Maternal outcomeNifedipine
n=201Placebon=205
HR [95% CI]
Prolongation of pregnancy (days)
31 (8 – 57) 35 (7 – 61) 1.1 [0.86 to 1.3]
Gestational age at delivery (wks)
34.1 ± 4.0 34.2 ± 4.0 1.0 [0.83 to 1.2]
RR [95% CI]
Maternal side effects – no. (%)
6 (3) 5 (2) 1.2 [0.38 to 4.0]
Intrauterine infection – no. (%)
13 (7) 15 (7) 0.88 [0.43 to 1.8]
Post partum bleeding (ml) 400 (200 – 600)
300 (200 – 500)
p=0.10
Hemorrhage > 1L – no. (%)
22 (11) 15 (7) 1.5 [0.80 to 2.8]
Delivered within study period n=59 n=61
Post partum bleeding (ml) 400 (300 – 700)
300 (200 – 525)
p=0.04
Hemorrhage > 1L – no. (%)
8 (14) 3 (5) 2.6 [0.73 to 9.3]
Maternal outcomeNifedipine
n=201Placebon=205
HR [95% CI]
Prolongation of pregnancy (days)
31 (8 – 57) 35 (7 – 61) 1.1 [0.86 to 1.3]
Gestational age at delivery (wks)
34.1 ± 4.0 34.2 ± 4.0 1.0 [0.83 to 1.2]
RR [95% CI]
Maternal side effects – no. (%)
6 (3) 5 (2) 1.2 [0.38 to 4.0]
Intrauterine infection – no. (%)
13 (7) 15 (7) 0.88 [0.43 to 1.8]
Post partum bleeding (ml) 400 (200 – 600)
300 (200 – 500)
p=0.10
Hemorrhage > 1L – no. (%)
22 (11) 15 (7) 1.5 [0.80 to 2.8]
Delivered within study period n=59 n=61
Post partum bleeding (ml) 400 (300 – 700)
300 (200 – 525)
p=0.04
Hemorrhage > 1L – no. (%)
8 (14) 3 (5) 2.6 [0.73 to 9.3]
Data are presented as mean ± SD or median (IQR: 25th to 75th percentile)
(favors nifedipine) (favors placebo)
1 2 50.50.2
Relative Risk
95% CI
0.85 [0.26-2.7]
0.1 10
Adverse neonatal outcome
CLD
PVL
IVH
5/201 66/205
2/201 5/205
0/201 0/205
Total 24/201 28/205
Nifedipine Placebo
0.92 [0.53-1.5]
NEC 5/201 33/205
Sepsis 16/201 18/205
Death 5/201 44/205
NA
1.7 [0.41-7.0]
0.91 [0.48-1.7]
1.3 [0.35-4.7]
0.41 [0.08-2.1]
Neonatal outcomeNifedipine
n=245Placebon=257
p-value
Birth weight (g) 2047 (1950 – 2149)
2035 (1938 – 2138)
0.88
Ventilation support
n=35 n=34
Number of days 2 (1 – 4) 3 (1 – 6) 0.25
NICU admission n=100 n=102
Number of days 10 (6 – 19) 10 (5 – 24) 0.76
Hospital admission
n=216 n=220
Number of days 23 (5 – 42) 23 (4 – 45) 0.84
Data are presented as median and IQR (25th to 75th percentile)
Conclusion
Sustained tocolysis with nifedipine
neither prolongs pregnancy nor
improves perinatal outcome
Nifedipine is not useful beyond
48 hours of initial tocolysis for
corticosteroid induced lung
maturation
Strengths
Large nationwide study
No additional tocolysis
Limitations
Low incidence of adverse
perinatal outcome
ACKNOWLEDGEMENT
Patients APOSTEL-II trialTrial group APOSTEL-II
ZonMwACE Pharmaceuticals
Pharmacy Haga Ziekenhuizen All research nurses and midwives
Consortium board and staffAll gynecologists, residents, midwives and
nurses of the participating centers
www.studies-obsgyn.nl/apostel2
Back-up slides
Eligible (n=640)
Non-randomization (n=234) Sustained tocolysis (n=8) No sustained tocolysis (n=226)
Lost-to-follow-up (n=0) Rescue tocolysis (n=9)
Nifedipine (n=201)
Placebo (n=205)
Lost-to-follow-up (n=0) Rescue tocolysis (n=8)
Allocation
Analysis
Randomized (n=406)
Exclusion
Analyzed (n=205)
Analyzed (n=201)
Statistics
To detect a reduction of 11% in adverse
perinatal outcome, we needed to enroll 406
patients
Intention-to-treat analysis
Data Safety Monitoring Committee Interim analysis after 200 patients
Baseline characteristics at randomizationRandomization
n=406
Nifedipinen=201
Placebon=205
Age – yrs 30.2 ± 5.1 30.2 ± 5.1
Body Mass Index # 23.3 ± 4.7 23.2 ± 4.0
Caucasian 170 (86) 152 (77)
Nulliparous 114 (58) 102 (52)
Previous preterm birth
38 (19) 52 (26)
Gestational age – weeks
29.2 ± 1.7 29.2 ± 1.8
Multifetal gestation 41 (21) 43 (22)
PPROM 53 (27) 49 (25)
Vaginal bleeding 38 (19) 38 (19)
Vaginal examinationDilatation (cm)
n=1301.1 ± 1.5
n=1321.4 ± 1.6
Cervical length (mm) 24.8 ± 12.6 23.5 ± 11.2
EducationHigher professional
n=11749 (42)
n=11741 (35)
Smoking 0 (0) 1 (1)# kg/m2
Baseline characteristics at randomizationRandomization
n=406Non-
randomization n=234
Nifedipinen=201
Placebon=205
Age – yrs 30.2 ± 5.1 30.2 ± 5.1 29.0 ± 5.5
Body Mass Index # 23.3 ± 4.7 23.2 ± 4.0 23.6 ± 5.0
Caucasian 170 (86) 152 (77) 161 (83)
Nulliparous 114 (58) 102 (52) 124 (58)
Previous preterm birth
38 (19) 52 (26) 39 (15)
Gestational age – weeks
29.2 ± 1.7 29.2 ± 1.8 28.9 ± 4.3
Multifetal gestation 41 (21) 43 (22) 45 (21)
PPROM 53 (27) 49 (25) 40 (19)
Vaginal bleeding 38 (19) 38 (19) 43 (20)
Vaginal examinationDilatation (cm)
n=1301 (0 – 2)
n=1321 (0 – 2)
n=1021.0 ± 1.3
Cervical length (mm) 26 (10 - 30) 24 (17 - 31) 24.0 ± 12.0
EducationHigher professional
n=11749 (42)
n=11741 (35)
n=7634 (45)
Smoking 0 (0) 1 (1) 0 (0)# kg/m2
Maternal outcomeNifedipine
n=201Placebon=205
HR/RR (95% CI)
Gestational age at delivery (wks)
34.0 ± 4.0 34.1 ± 4.0 1.02 (0.83 to 1.24)
Prolongation of pregnancy (days)
28 (7 – 57) 35 (7 – 61) 1.03 (0.85 to 1.26)
Delivery <32 weeks 67 (34) 70 (36) 0.95 (0.73 to 1.25)
Delivery <34 weeks 97 (49) 93 (47) 1.04 (0.85 to 1.27)
Delivery <37 weeks 135 (68) 131 (66) 1.03 (0.89 to 1.18)
Rescue tocolysis
Maternal side effects
Intrauterine infection
Cesarean section
Post partum hemorrhage (ml)
Post partum hemorrhage (ml)(delivered within study period)
Data are presented as mean ± SD, no. (%) or median (IQR: 25th to 75th percentile)
Maternal outcomeNifedipine
n=201Placebon=205
HR/RR (95% CI)
Gestational age at delivery (wks)
34.0 ± 4.0 34.1 ± 4.0 1.02 (0.83 to 1.24)
Prolongation of pregnancy (days)
28 (7 – 57) 35 (7 – 61) 1.03 (0.85 to 1.26)
Delivery <32 weeks 67 (34) 70 (36) 0.95 (0.73 to 1.25)
Delivery <34 weeks 97 (49) 93 (47) 1.04 (0.85 to 1.27)
Delivery <37 weeks 135 (68) 131 (66) 1.03 (0.89 to 1.18)
Rescue tocolysis 9 (4.5) 8 (3.9) 1.15 (0.45 to 2.91)
Maternal side effects 5 (3) 4 (2) 1.24 (0.34 to 4.56)
Intrauterine infection 13 (7) 15 (8) 0.86 (0.42 to 1.76)
Cesarean section 52 (27) 54 (28) 0.96 (0.69 to 1.33)
Post partum hemorrhage (ml)
400 (200 – 600)
300 (200 – 500)
p=0.10
Post partum hemorrhage (ml)(delivered within study period)
400 (300 – 700)
300 (200 – 525)
p=0.04Data are presented as mean ± SD, no. (%) or median (IQR: 25th to 75th percentile)
Neonatal outcomeNifedipine(n=201)n=241
Placebo(n=205)n=244
RR (95% CI)
Composite adverse perinatal outcome
25 (10) 28 (11) 0.92 (0.54 to 1.55)
•Chronic Lung Disease
•Intraventricular Hemorrhage #
•Periventricular Leucomalacia *
•Necrotizing Enterocolitis
•Proven Neonatal Sepsis
•Perinatal death
# > grade II
* > grade I
Neonatal outcomeNifedipine(n=201)n=241
Placebo(n=205)n=244
RR (95% CI)
Composite adverse perinatal outcome
25 (10) 28 (11) 0.92 (0.54 to 1.55)
•Chronic Lung Disease 5 (2) 5 (2) 1.01 (0.3 to 3.45)
•Intraventricular Hemorrhage #
1 (0) 4 (2) 0.25 (0.03 to 2.25)
•Periventricular Leucomalacia *
0 0 n.a.
•Necrotizing Enterocolitis 5 (2) 7 (3) 0.9 (0.24 to 3.29)
•Proven Neonatal Sepsis 16 (7) 17 (7) 0.96 (0.49 to 1.87)
•Perinatal death 5 (2) 6 (2) 0.84 (0.26 to 2.71)
Neonatal outcomeNifedipine(n=241)
Placebo(n=244)
p-value
Birth weight (g) 2182 ± 827 2183 ± 819 0.88
2128 2100
1518 - 2693 1475 - 2818
Ventilation support (days)
0.47 ± 1.61 0.80 ± 3.11 0.22
Median 0 0 0.81
IQR 0 - 0 0 - 0
NICU admission (days) 6.2 ± 12.5 7.4 ± 14.5 0.41
Median 0 0 0.68
IQR 0 – 8 0 – 9
Hospital admission (days)
20.3 ± 22.4 20.7 ± 22.9 0.79
Median 12 12 0.88
IQR 3 – 31 2 – 35