Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor APOSTEL-II trial

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

http://www.nccn.nl/nccn-en/images/common/umcradboud_logo.jpg

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)


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)


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


300 (200 – 525)

p=0.04


8 (14) 3 (5) 2.6 [0.73 to 9.3]


n=201Placebon=205

HR [95% CI]


31 (8 – 57) 35 (7 – 61) 1.1 [0.86 to 1.3]


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]


300 (200 – 500)

p=0.10


22 (11) 15 (7) 1.5 [0.80 to 2.8]

Delivered within study period n=59 n=61


300 (200 – 525)

p=0.04


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

http://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


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)


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


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)


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


n=201Placebon=205

HR/RR (95% CI)


34.0 ± 4.0 34.1 ± 4.0 1.02 (0.83 to 1.24)


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)



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)


n=201Placebon=205

HR/RR (95% CI)


34.0 ± 4.0 34.1 ± 4.0 1.02 (0.83 to 1.24)


28 (7 – 57) 35 (7 – 61) 1.03 (0.85 to 1.26)




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)


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)


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

Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor APOSTEL-II trial

Documents

Transcript of Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor APOSTEL-II trial