Tocolysis For Inhibiting Preterm Birth in Extremely Preterm Birth, Multiple Gestations and in Growth-Restricted Fetuses A Systematic Review and Meta-Analysis
Tocolysis For Inhibiting Preterm Birth in Extremely Preterm Birth, Multiple Gestations and in Growth-Restricted Fetuses A Systematic Review and Meta-Analysis
Tocolysis For Inhibiting Preterm Birth in Extremely Preterm Birth, Multiple Gestations and in Growth-Restricted Fetuses A Systematic Review and Meta-Analysis
Abstract
This systematic review was to identify available evidence on the effectiveness of tocolysis in inhibiting preterm
delivery for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies, and
their infants’ outcomes. A comprehensive search using MEDLINE, Embase, the Cochrane Library, CINAHL, POPLINE
and the WHO Global Health Library databases was conducted on 14 February 2014. For selection criteria,
randomized controlled trials and non-randomized studies that compared tocolysis treatment to placebo or no
treatment were considered. Selection of eligible studies, critical appraisal of the included studies, data collection,
meta-analyses, and assessment of evidence quality were performed in accordance with the Cochrane
Collaboration’s guidance and validated assessment criteria. The search identified seven studies for extremely
preterm birth, in which three were randomized controlled trials (RCTs) and four were non-randomized studies
(non-RCTs). There were no eligible studies identified for women with multiple pregnancy and growth-restricted
fetuses. Meta-analyses indicated no significant difference was found for the relative effectiveness of tocolytics
versus placebo for prolonging pregnancy in women with extremely preterm birth (RR 1.04, 95 % CI 0.83 to 1.31)
or reducing the rate of perinatal deaths (RR 2.22, 95 % CI 0.26 to 19.24). In summary, there is no evidence to draw
conclusions on the effectiveness of tocolytic therapy for women with threatened extremely preterm birth, multiple
gestations, and growth-restricted babies.
Keywords: Extremely preterm birth, Growth-restricted babies, Meta-analysis, Multiple gestations, Non-randomized
studies, Perinatal death, Prolongation of pregnancy, Randomized controlled trials, Tocolysis
© 2016 Miyazaki et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Miyazaki et al. Reproductive Health (2016) 13:4 Page 2 of 12
Identification
Records identified via the database that meet
review questions, Q1, Q2, and Q3, with
duplicates removed
(N =1506)
Q1=22
for reasons such as head-to-
Q2=14
head comparison treatment,
Q3=1
comparison between
(n = 37)
singleton and twins or
prophylactic trials studies
(see Additional file 2).
(n = 30)
Studies included in
qualitative synthesis
Q1=7
Included
Q2=0
Q3=0
(N =7)
bias. The summary of risk of bias within studies is [21] but there was no significant difference in the rate
presented in an additional file (see Additional file 3). of prolonging the pregnancy between the tocolysis
(atosiban) group and the placebo group (RR 1.15,
Randomized controlled trials of tocolytic treatment for 95 % CI 0.81 to 1.63, 77 women) (Table 2). For
extremely preterm birth prolongation of pregnancy more than 48 h, there
Three RCTs for preterm birth including subset groups were two trials [21, 23] and the meta-analysis showed
of women with extremely preterm birth were identified that there was no relative risk difference found
(Table 1). The three RCTs had a total of 1249 women between the tocolysis group and the placebo group
and these women were with pregnancies from less than (RR 1.04, 95 % CI 0.83 to 1.31, I2 = 0 %, 117 women).
28 weeks up to 35 weeks. All trials evaluated the use of The effect estimate and the confidence interval
tocolysis compared to placebo with a follow-up to deliv- crossed the line of no effect (Fig. 2a). There were no
ery. Women with threatened extremely preterm labour evident heterogeneity and inconsistency indicated
with less than 28 weeks of gestation were recruited into among the studies.
the trials due to uterine contractions and/or cervical
changes (e.g. dilatation or shortening). Two trials used Prolongation of pregnancy more than 7 days for extremely
atosiban in the treatment arm, and one trial used preterm birth (RCTs)
ritodrine. The subset results form the total population in For prolongation of pregnancy more than 7 days,
regard to the effectiveness of tocolysis for extremely there were two trials [21, 23] and the pooled relative
preterm birth (less than 28 weeks of gestation) were risk indicated no difference between the tocolysis
extracted from two trials for meta-analyses [21, 22]. group and the placebo group (RR 1.05, 95 % CI 0.75
to 1.48, I2 = 48 %, 117 women). The effect estimate
Prolongation of pregnancy more than 24 and 48 h for and the confidence interval crossed the line of no
extremely preterm birth (RCTs) effect (Fig. 2b). There was a substantial heterogeneity
Prolongation of pregnancy more than 24 h in women in this comparison and a moderate inconsistency
with extremely preterm birth was found in one trial across the studies.
Miyazaki et al. Reproductive Health (2016) 13:4
Table 1 Characteristic of included studies (Randomized controlled trials)
Extremely preterm birth (less than 28 weeks of gestation)
Study ID Country Study design Sample size (groups) Description of women/patients Intervention (Description) Comparison (Description) Outcomes
with preterm labour
Richter 2005 [23] Germany Prospective-RT 40 (n = 20 vs. n = 20) Women, 31–42 years of age, Atosiban Placebo Prolongation of
between 18 to 24th week of pregnancy >48 h
gestation and with uterine
(Initial intravenous infusion of (Intravenous infusion Prolongation of
contractions duration >30 s,
rate ≥ 4/30 min. Cervical 6.75 mg of atosiban in 0.9 ml of saline solution) pregnancy >7 days
effacement >50 % and cervical of sodium chloride, and followed
by high dosage of infusion
dilatation of 0–3 cm (nulliparous),
(300 lg/ min) for 3 h and then
and 1–3 cm (primiparous and
multiparous) low dosage (100 lg/min) up
to 45 h.)
Romero 2000 [21] USA RCT 501 (n = 250 vs. n = 251) Women between gestational Atosiban Placebo Prolongation of
age of 20 weeks to 33 weeks, pregnancy >24 h
with intact membranes, cervical
77 a (n = 43 vs. n = 34) (Initial intravenous infusion of (Matching placebo Prolongation of
dilatation of 1 to ≤3 cm, preterm
6.75 mg of atosiban over 1 min contained same pregnancy >48 h
labor required the presence
of ≥4 uterine contractions and followed by an infusion of formulation minus
Prolongation of
over 30 min, each lasting 300 μg/min of atosiban for 3 h, the 5 % mannitol
and then 100 μg/min for up solution of atosiban.) pregnancy >7 days
at least 40 s.
to 45 h.) Perinatal death
The Canadian PLIG 1992 [22] Canada RCT 708 (n = 352 vs. n = 356) Women between gestational Ritodrine Placebo Perinatal death
age of 20 to 35 weeks, with
151 a (n = 76 vs. n = 75) uterine contractions four per (Intravenous infusion of ritodrine (Dextrose solution
in 5 % dextrose at a rate of 0.35 alone without ritodrine)
20 min or six per 60 min or
mg/min until the cessation of
any uterine activity with ether
rupture membranes or cervical uterine activity, the failure
dilatation by 2 cm or more. of therapy, or occurrence of
impermissible maternal
side effects
Multiple gestations
No report found for tocolytic treatment for imminent risk of preterm labor
Growth-restricted fetuses
No report found for tocolytic treatment for imminent risk of preterm labor
a
Subset of < 28 weeks of gestation sample size extracted from total participant in the study; (n = intervention group vs. n = comparison group); perspective-RT, prospective randomized trial
Page 5 of 12
Miyazaki et al. Reproductive Health (2016) 13:4 Page 6 of 12
Table 2 A summary of effect size for tocolytic treatment versus placebo for extremely preterm birth outcomes in RCTs
Tocolysis compared to placebo in women with extremely preterm birth (RCTs)
Patient or population: Women with extremely preterm birth
Intervention: Tocolysis (atosiban and ritodrine)
Comparison: Placebo
Outcomes Anticipated absolute Relative effect № of participants Quality of the
effectsf (95 % CI) (95 % CI) (studies) evidence (GRADE)
Risk with placebo Risk with tocolysis
Prolongation of pregnancy >24 h Study population RR 1.15 (0.81 to 1.63) 77 (1 RCT) ⨁⨁⨁ MODERATE a
59 per 100 68 per 100 (476 to 959)
Prolongation of pregnancy >48 h Study population RR 1.40 (0.83 to 1.31) 117 (2 RCTs) ⨁ VERY LOW a,b
Perinatal death in extremely preterm birth (RCTs) study [23] did not mention allocation concealment,
Two RCTs [21, 22] reported on outcome of perinatal which the limitation of the trial decrease the confidence
deaths and their combined perinatal deaths were 50 in the estimated results. The quality of evidence for
out of a total of 265 fetuses. The relative risk from outcome of perinatal death was rated very low as well
these combined trials was RR 2.22, 95 % CI 0.26 to because of significant heterogeneity attributed by small
19.24, I2 = 77 %, 265 fetuses (Fig. 2c). This estimate sample size and the overall estimate had wide confidence
suggested that there was an increase risk of perinatal interval, which indicated substantial uncertainly. The
death with tocolytic treatment relative to placebo summary of quality of evidence is presented in GRADE
group, but the estimate showed statistical uncertainty tables (see Additional file 4).
due to wide confidence interval that crossed the line
of no effect. A substantial heterogeneity and incon- Non-randomized studies of tocolytic treatment for
sistency were indicated among the studies. extremely preterm birth
Four non-RCTs of tocolytic treatment for women with
Quality of the evidence from (RCTs) for extremely preterm extremely preterm labour were identified and they were
birth all retrospective cohorts by design [24–27]. The identi-
The quality of evidence for prolongation of pregnancy fied non-RCTs evaluated tocolytic treatment versus to
more than 24 h was rated to be moderate. However, the treatment, and two of the studies [24, 27] included
evidence for prolonging pregnancy more than 48 h or cerclage with tocolysis treatment. Of the four studies,
more than 7 days were rated very low due to small three studies [24, 25, 27] included information of 471
sample size, which contributed to imprecision, and one women who were at 14 to 23.9 weeks of pregnancy and
Miyazaki et al. Reproductive Health (2016) 13:4 Page 7 of 12
Perinatal death
Fig. 2 Forest plot for prolongation of delivery and perinatal death with RCTs that compared tocolytic treatment versus placebo for extremely
preterm birth
one study [26] included only the information of 138 for 7 days or more after admission (RR 2.13, 95 % CI
neonates of whom the mothers were at less than 1.12 to 4.06, 148 women; NNT = 6, 95 % CI 3.2 to 23.5)
29 weeks of pregnancy (Table 3). In regard to the types (Table 4).
of tocolytics, three of the studies [24, 26, 27] evaluated
indomethacin and one of the studies [25] evaluated any Prolongation of pregnancy more than 24, 28, 32, or
tocolytic medication (e.g. magnesium sulfate, indometh- 35 weeks for extremely preterm birth (non-RCTs)
acin, nifedipine, used singly or in combination). The One study [24] reported that there was no difference in
main outcomes and the unadjusted relative risks from the rate of prolonging pregnancy for more than 24 weeks
these non-RCTs are presented in Table 4. The other (RR 0.91, 95 % CI 0.76 to 1.09, 101 women); meanwhile,
outcomes, such as birth weight more than 1500 grams, another study [27] also reported no significant difference
intraventricular hemorrhage, necrotizing enterocolitis was found in the rate of prolonging pregnancy for more
and patent ductus arteriosus, are presented in additional than 28 weeks (RR 0.91, 95 % CI 0.69 to 1.20, 222
file (see Additional file 4). women) between the tocolytic treatment group and the
no treatment group. Two non-RCTs reported on pro-
Prolongation of pregnancy more than 7 days for extremely longation of pregnancy for more than 32 weeks: one
preterm birth (non-RCTs) study [27] showed that there was no difference found in
One non-RCTs [25] reported there was a relative differ- the tocolytic treatment group relative to that in the no
ent in rate between the tocolytic treatment group and treatment group (RR 0.94, 95 % CI 0.68 to 1.30, 222
the no treatment group for women remaining pregnant women) and another study [24] also showed a similar
Miyazaki et al. Reproductive Health (2016) 13:4
Table 3 Characteristics of included studies (Non-randomized studies)
Extremely preterm birth (less than 28 weeks of gestation)
Study ID Country Study design Sample size Description of women/patients Intervention (description) Comparison Outcome
with preterm labour
Berghella 2009 [27] USA Retrospective cohort 222 (n = 68 vs. Women between 14 and Indomethancin plus No treatment plus some Prolongation of
(January 1998 - n = 154) 25 week of gestation with some with cerclage with cerclage pregnancy >28, 32,
December 2005) suspected cervical dilation or 35 weeks
≥1 cm.
(50 mg orally, followed Perinatal death
by 25 mg orally every
6 h for a maximum Birth weight >1500 grams
of 48 h)
a
Cape 2010 [26] USA Retrospective cohort 138 neonates All women less than Indomethancin No treatment Neonatal outcomes only
(2003–2008) (n = 69 vs. 29 weeks of gestation including intraventricular
n = 69) with threaten with hemorrhage, necrotizing
premature rupture of enterocolitis, patent ductus
membranes. arteriosus, and spontaneous
intestinal perforations
Manuck 2012 [25] USA Retrospective cohort 148 (n = 84 vs. Women with a singleton Tocolytic medication No treatment Prolongation of
(January 2000 – June n = 64) non-anomalous fetus with pregnancy >7 days
2011) spontaneous preterm
(Database record of Perinatal death
labour and intact membranes,
tocolytic treatment used
between 20–23.9 week of
gestation, and with cervical i.e. magnesium sulfate,
dilation ≥ 1 cm and effaced indomethacin or nifedipine,
either used singly or in
> 50 %.
combination)
Visintine 2008 [24] USA Retrospective cohort 101 (n = 51 vs. Asymptomatic women Indomethacin plus cerclage Cerclage only Prolongation of
(1995–2006) n = 50) followed from 14 weeks pregnancy >24, 32,
(50 mg initially orally
through 23 weeks or 35 weeks
6 days gestation with a or rectally, followed by
short cervical length, 25 mg orally every 6 h
for about 48 h.)
defined as <25 mm,
placed with an
ultrasound-indicated
cerclage.
Multiple gestations
No report found for tocolytic treatment for imminent risk of preterm labor
Growth-restricted fetuses
No report found for tocolytic treatment for imminent risk of preterm labor
Page 8 of 12
a
Sample size of infants exposed to in utero indomethancin within 4 weeks of delivery (n = intervenetion group vs. n = comparison group)
Miyazaki et al. Reproductive Health (2016) 13:4
Table 4 A summary of results for tocolytic treatment versus no treatment for extremely preterm birth outcomes in non-RCTs
Tocolysis compared to no treatment for women with extremely preterm birth (non-RCTs)
Patient or population: Women with extremely preterm birth
Intervention: Tocolysis
Comparison: no treatment
Outcomes Anticipated absolute effects h(95 % CI) Relative effect (95 % CI) № of participants (studies) Quality of the evidence (GRADE)
Risk with no treatment Risk with tocolysis
Prolongation of pregnancy >7 days Study population RR 2.13 (1.12 to 4.06) 148 (1 non-RCT) ⨁ VERY LOW a,b
Page 9 of 12
g
This information was from a study with unclear risk of selection of participants, measurement of exposure, incomplete data and selective reporting
CI Confidence interval; RR Risk ratio; OR Odds ratio
h
The risk in the intervention group (and its 95 % confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95 % CI)
Miyazaki et al. Reproductive Health (2016) 13:4 Page 10 of 12
findings (RR 0.95, 95 % CI 0.73 to 1.24, 101 women). Randomized controlled trials and non-randomized studies
When the relative effect from these two non-RCTs of tocolytic treatment for multiple gestations
[24, 27] were pooled, the overall estimate showed that There were no eligible studies found for tocolytic treat-
there was no significant difference between the tocoly- ment trials for inhibiting preterm birth for women with
sis (indomethacin) group and the no treatment group multiple pregnancies.
(RR 0.94, 95 % CI 0.76 to 1.17, I2 = 0 %, 323 women)
(Table 4). Two non-RCTs [24, 27] reported on pro- Randomized controlled trials and non-randomized studies
longation of pregnancy for more than 35 weeks. One of tocolytic treatment for growth-restricted fetuses
study [27] showed that there was no significant There were no eligible studies found for tocolytic
difference found between the two comparison groups treatment for inhibiting preterm birth for women with
(RR 1.01, 95 % CI 0.68 to 1.48, 222 women), and growth-restricted fetuses, except a prophylactic con-
similar result was reported in the other study [24] (RR trolled clinical trial for growth-restricted fetuses was
0.92, 95 % CI 0.68 to 1.24, 101 women). The overall identified [28].
effect estimate from these two non-RCTs [24, 27]
indicated that there was no relative effect difference Discussion
found between the tocolytic treatment group and the Tocolytics for preterm labour has been documented in
no treatment group (RR 0.96, 95 % CI 0.75 to 1.23, clinical recommendations and guidelines; however, they
I2 = 0 %, 323 women) (Table 4). do not distinguished extremely preterm birth, multiple
pregnancy and growth-restricted fetuses. This systematic
Perinatal death in extremely preterm birth (non-RCTs) review was to gather any available evidence of tocolytic
Perinatal deaths were reported in two studies [25, 27] treatment for specific group of women with imminent
(Table 4). One study [27] showed that there was no risk of preterm labour under extremely preterm, mul-
significant difference found in the rate of neonatal tiple pregnancy and growth-restricted fetuses conditions
survival (RR 1.12, 95 % CI 0.92 to 1.37, 222 fetuses) inclusively from RCTs and non-RCTs studies.
and the same indicated that there was no significant The meta-analysis data from the RCTs for women with
difference in the rate of perinatal deaths as well (RR extremely preterm labour showed that prolongation of
0.81, 95 % CI 0.54 to 1.21, 222 fetuses). The other pregnancy between tocolysis and placebo groups was
study [25], in which several tocolytic were used, largely uncertain since the prediction interval crossed
showed that there was a significance difference found the line of no effect. The overall effect estimate from
in the rate of perinatal deaths and reported that the these trials may not entirely represent only women with
tocolysis group had 36.6 % of perinatal deaths as premature cervical dilation since one of the trial [23]
opposed to 62.5 % in the no treatment group (RR included women with less then 20 weeks of gestation
0.65, 96%CI 0.45 to 0.94,148 fetuses; NNT = 6, 95 % and the condition was connected with threaten miscar-
CI 2.9 to 3.28, 148 fetuses). The overall effect esti- riage, preterm rupture of the membranes or infection
mate from the two non-RCTs [25, 27] showed a after the trial enrollment. In addition, the subset data of
significant difference in reducing the rate of perinatal women with less than 28 weeks of gestation was ex-
deaths (RR 0.73, 95 % CI 0.55 to 0.95, I2 = 0 %, 370 tracted from the larger preterm population, which could
fetuses) and the pooled estimate implied that tocolytic not be statistically powered for evaluating possible differ-
treatment decreases the risk of perinatal deaths by ential effects of the treatment due to small population
27 % (Table 4). size. Although the evidence was rated to be very low
quality (one study without allocation and small popula-
Quality of the evidence from (non-RCTs) for extremely tion size), the analysis retained the fact that there was no
preterm birth definite evidence found for tocolytic treatment to be
The quality of evidence for prolongation of pregnancy effective in prolonging pregnancy for women at less than
for more than 7 days or 24, 28,32 and 35 weeks was 28 weeks of pregnancy and including those with high
rated very low because majority of the information were risk of miscarriage. This estimate was comparable to a
from studies with unclear risk of bias in the incomplete systematic review, which also documented that uterine
outcome data and high risk of bias in selective reporting muscle relaxant drugs for women with threatened mis-
and confounding variable. The quality of evidence for carriage for 170 women did not show to be effective in
perinatal death was rated very low since the information preventing preterm birth [29].
was from two studies with unclear risk of bias for In regard to perinatal outcomes, perinatal death was pri-
incomplete outcome data and selective reporting and marily evaluated since neonatal and infant outcomes were
one study was with high risk of bias for confounding too few as expected and were not distinguished clearly by
variables (see Additional file 4). gestational weeks or whether was from extremely preterm
Miyazaki et al. Reproductive Health (2016) 13:4 Page 11 of 12
birth. The meta-analysis for perinatal death lacked the specified; therefore, caution is needed when interpreting
power to detect statistical significance due to substantial some of these results.
heterogeneity found among the studies and too few Serious harm was not reported among the RCTs, as
studies available to overcome such statistical requirement. no maternal death occurred during the intervention
The reason for such apparent heterogeneity could be the period, though other adverse events, such as chest
criteria difference in administrating alternative treatment pain or tachycardia, were commonly reported. In the
across the studies, such as antenatal corticosteroids or non-RCTs, harm assessment were not mentioned, but
glucocorticoid treatment. In the trial of using atosiban one study[26], in which newborns were exposed to
[21], 54 % of the treatment group received antenatal indomethacin, reported a trend for patent ductus
corticosteroids before 28 weeks of gestation after arteriosus surgical ligation (aHR 1.41, 95 % CI 0.93 to
randomization in contrast with the ritodrine trial [22], 2.14). For the most part, results from both RCTs and
where a proportion of women received full glucocorticoid non-RCTs were reaching to parallel speculation in
treatment before randomization. Rescue treatments or terms of the effectiveness of tocolysis for prolongation
additional treatments were the prominent cofounding of pregnancy and reducing the rate of perinatal
factors, and future studies would need to consider covari- deaths under extremely preterm birth.
ance adjustment especially for imbalance baseline variable
from the subset data. Apart from insufficient data to Conclusions
determine the true effect on perinatal death in extremely There was no apparent effectiveness found for tocoly-
preterm birth, the administration of tocolytic treatments tic treatment to inhibit preterm birth for women with
started on average at about 20 weeks of pregnancies extremely preterm condition or to reduce perinatal
estimated a trend towards no desirable benefit for redu- deaths, and there were no eligible studies found in
cing the risk of perinatal deaths. This observation was regard to tocolytic treatment for multiple gestation
similar to the other systematic review reports on tocolysis and women with growth-restricted fetuses. Evidence
in preterm birth management (less than 34 weeks of from this review was not sufficient to provide specific
gestation) which also suggested no significant difference recommendations for women with extremely preterm
was found in perinatal death [8, 30]. birth, and no conclusion could be drawn on the ben-
In the non-RCTs, tocolytic treatment for women with efits or harms of tocolytic therapy in women carrying
threatened extreme preterm labour did not indicate multiple pregnancies or growth-restricted fetuses at
effectiveness in prolonging pregnancy for more than 24, imminent risk of preterm birth. This review provided
28, 32 and 35 weeks based on each individual reporting. a trend of generic evidences that tocolysis is highly
Although one of the non-RCT [25] showed a significant uncertain to be effective; therefore, practitioners and
difference for prolonging pregnancy more than 7 days in policy makers should reflect on its application to
women at 20 to 24 weeks of pregnancy, the average these populations.
gestational age at delivery was 24.2 weeks in the tocoly-
sis group and 23.2 weeks in the no treatment group. Additional files
This report suggested that tocolytic treatment could not
effectively inhibit extremely preterm birth or prolong Additional file 1: Search strategy. (DOCX 41 kb)
the pregnancy to term delivery [5]. For outcome of Additional file 2: Excluded studies with reasons. (DOCX 126 kb)
perinatal death, two non-RCTs using indomethacin with Additional file 3: Risk of bias within studies. (DOCX 188 kb)
cerclage treatment for extremely preterm birth reported Additional file 4: GRADE tables. (DOCX 134 kb)
different observations. One study [27] reported no
significant difference in the rate of perinatal death under Abbreviations
aHR: adjusted hazard ratio; aOR: adjusted odd ratio; aRR: adjusted risk ratio;
indomethacin, whereas the other study [25] implied that
CI: confidence interval; GRADE: Grades of Recommendation, Assessment,
there was a significant difference in reducing the risk of Development and Evaluation Working Group; non-RCTS: non-randomized
perinatal death under several types of tocolytics (single studies; NNT: Numbers needed to treat; OR: odd ratio; RCT: randomized
controlled trial; RoBANS: risk of Bias Assessment Tool for Nonrandomized
or combined) used. The report on a lower rate of
Studies; RR: Risk ratio; WHO: World Health Organization.
perinatal death found in tocolysis group was suggested by
the short time gain from tocolytic treatments that in- Competing interests
creased the opportunity for providing antenatal cortico- The authors have no conflicts of interest or other financial disclosures to
declare.
steroid treatment during the intervention. This particular
study did not indicate confounding variables adjustment Authors’ contributions
(e.g. women receiving one or women receiving more types CM carried out the identification of studies, data extraction and meta-
analysis, data interpretation and the drafting and critical revision of the
of tocolytic were not specified) and the rate of neonatal manuscript. RMG carried out the identification of studies, data extraction and
death after receiving antenatal corticosteroids was not analysis and helped to draft the manuscript. EO participated in its design
Miyazaki et al. Reproductive Health (2016) 13:4 Page 12 of 12
and coordination and helped to revise the manuscript. TS carried out the 14. Morrison JJ, Rennie JM. Clinical, scientific and ethical aspects of fetal and
search of literature and coordinated the search strategy. OTO and RM neonatal care at extremely preterm periods of gestation. Br J Obstet
conceived of the study, and participated in its design and coordination Gynaecol. 1997;104:1341–50.
and helped to revise the manuscript for important intellectual content. 15. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States
All authors read and approved the final manuscript. national reference for fetal growth. Obstet Gynecol. 1996;87:163–8.
16. Hediger ML, Scholl TO, Schall JI, Miller LW, Fischer RL. Fetal growth and the
etiology of preterm delivery. Obstet Gynecol. 1995;85:175–82.
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1
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Development, Tokyo, Japan. 2Graduate School of Human Sciences, Osaka 22. The Canadian Preterm Labor Investigators Group. Treatment of
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