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International Journal of Gynecology and Obstetrics xxx (2014) xxxxxx

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International Journal of Gynecology and Obstetrics

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CLINICAL ARTICLE

Maintenance tocolysis with oral micronized progesterone for prevention

of preterm birth after arrested preterm labor
Manju Choudhary a,, Amita Suneja a, Neelam B. Vaid a, Kiran Guleria a, M.M.A. Faridi b
a
Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India
b
Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To evaluate the efcacy of maintenance therapy with oral micronized progesterone (OMP) for pro-
Received 29 August 2013 longation of pregnancy in cases of arrested preterm labor. Methods: Ninety women at 2434 weeks of singleton
Received in revised form 21 January 2014 pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n = 45)
Accepted 27 March 2014 or placebo (n = 45) daily until 37 weeks or delivery, whichever was earlier. Outcome parameters were com-
pared using Student t test, 2 test, Fisher exact test, and log-rank 2 test. Results: OMP signicantly prolonged
Keywords:
the latency period (33.29 22.16 vs 23.07 15.42 days; P = 0.013). Log-rank analysis revealed a signicant
Maintenance tocolysis
Oral micronized progesterone
difference in mean time to delivery between the 2 groups (P = 0.014). There were signicantly fewer preterm
Preterm labor births (33% vs 58%; P = 0.034) and low birth weight neonates (37% vs 64%; P = 0.017), and signicantly higher
mean birth weight (2.44 0.58 vs 2.14 0.47 kg; P = 0.009) in the OMP group. Perinatal outcomes and adverse
effects were similar in the 2 groups. Conclusion: Maintenance tocolysis with OMP signicantly prolonged preg-
nancy and decreased the number of preterm births.
Clinical Trial Registry of India: CTRI/2011/10/002043.
2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.

1. Introduction number of trials comparing progesterone and placebo or other tocolytic

Preterm birth is the leading cause of neonatal morbidity and mor-
tality, accounting for 10% of neonatal mortality worldwide [1]. The
accepted treatment of preterm labor is acute tocolysis, which may pro-
long gestation by 27 daysproviding time for corticosteroid adminis-
tration and maternal transport to a facility with a neonatal intensive
care unit (ICU).
Considerable debate remains as to whether maintenance tocolysis
is appropriate after initial tocolysis for spontaneous preterm labor.
Various drugs with different dosage schedules and routes have been
used for maintenance tocolysis (-agonists, calcium-channel blockers,
magnesium, and atosiban) but no signicant prolongation of pregnancy
or improved perinatal outcome has been noted [25]. Progesterone has
been widely used as a uterine sedative in the prevention of preterm
labor but it has not been investigated thoroughly for maintenance
tocolysis. Few recent studies support the use of progesterone as a main-
tenance tocolytic [69].
Currently, there is insufcient evidence to advocate progesterone
for maintenance tocolysis among women with preterm labor, as the
Corresponding author at: Department of Obstetrics and Gynaecology, UCMS and GTB
Hospital, Delhi 110095, India. Tel.: +91 9868482424; fax: +91 11 22590495.
E-mail address: manjuchoudhary04lhmc@gmail.com (M. Choudhary).
drugs is small. More trials are needed for better assessment of the efca-
cy of progesterone as a maintenance tocolytic agent.
The aim of the present study was to evaluate the efcacy of mainte-
nance therapy with oral micronized progesterone for prolongation of
pregnancy in cases of arrested preterm labor.
2. Materials and methods
A double-blind, randomized, placebo-controlled trial was conducted
at the Department of Obstetrics and Gynaecology and the Department
of Pediatrics at University College of Medical Sciences (UCMS) and
Guru Teg Bahadur Hospital, Delhi, India, from October 1, 2010, to
April 30, 2012. Ethical clearance was obtained from the institutional
ethics committee.
Pregnant women at 2434 weeks of singleton pregnancy were re-
cruited after successful tocolysis with nifedipine therapy. Women with
multiple pregnancies, premature rupture of membranes, prepartum
hemorrhage, fetal growth restriction, fetal distress, fetal congenital
anomalies, and history of tocolytic treatment were excluded from
the study.
After written informed consent was obtained, all women with
threatened preterm labor underwent detailed history-taking pertaining
to risk factors for preterm labor and examination (general physical
examination, obstetric examination, speculum examination, vaginal

http://dx.doi.org/10.1016/j.ijgo.2014.01.019
0020-7292/ 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.

Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after
arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
2 M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxxxxx

examination, and Bishop score). Preterm labor was dened as 4 contrac-
tions per 20 minutes or 8 per 60 minutes associated with progressive
change in cervix or cervical dilation of more than 1 cm or at least 80%
cervical effacement [10].
All women with threatened preterm labor received intravenous hy-
dration therapy (500 mL of intravenous lactated Ringer solution),
betamethasone (12 mg intramuscularly, followed by another 12 mg
after 24 hours), and tocolysis with nifedipine per hospital protocol
(initial dose of 20 mg, followed by 1020 mg every 46 hours).
Nifedipine tocolysis was continued until uterine contractions had sub-
sided for at least 12 hours. After the arrest of preterm labor, patients
were recruited for the study within 48 hours of acute tocolysis. Arrested
preterm labor was dened as no uterine contractions for at least
12 hours on nifedipine tocolysis.
Recruited women underwent routine obstetric investigations and
special investigations (hemoglobin with total leucocyte count; urine
culture and sensitivity; high vaginal swab culture and sensitivity). The
purpose of the urine culture and the high vaginal swab culture was to
detect infections and treat them accordingly.
For double-blinding, women were randomly allocated by a third party
in a 1:1 ratio into 2 groupsmicronized progesterone or placebo
using computer-generated random number tables. Each participant was
assigned a consecutive serial number from 1.
Precoded, opaque, sealed envelopes containing capsules for 7 days
(200 mg of oral micronized progesterone or placebo) were given to
the patients on a weekly basis. Study drugs were provided by the phar-
maceutical company, and similar-looking placebo was prepared in the
Department of Pharmacology at UCMS using lactose as ller.
Once a patient had been stable in the hospital for 48 hours after
stopping nifedipine, she was discharged with instructions regarding
signs and symptoms of preterm labor. Each woman was given drugs
for 1 week at each visit and was asked to take a capsule orally once
daily at bed time, from recruitment to 37 weeks or delivery, whichever
was earlier.
Weekly follow-up was carried out for signs and symptoms of pre-
term labor and any fresh complaint related to adverse effects of the
medication. Both the patient and the investigator were blinded to the
study medication. Compliance in taking medication was checked by
asking participants to return empty envelopes to the third party on a
weekly basis.
Decoding of sealed envelopes was carried out at the time of data
analysis. Participants were divided into 2 groups: group 1 (patients
taking the active drug) and group 2 (patients taking placebo).
The primary outcome parameter was prolongation of pregnancy/
latency period (i.e. days gained until delivery). Secondary outcome
parameters were number of preterm births, birth weight, gestation-
al age at delivery, readmission for preterm labor, neonatal ICU
admission, neonatal ICU stay, and neonatal morbidity (respiratory
distress syndrome, sepsis, necrotizing enterocolitis, and early neonatal
mortality).
For the sample size calculation, we assumed a standard deviation of
12 days, based on data from a previous study of maintenance tocolysis
[6]. Forty-two patients per group were needed to detect a 12-day differ-
ence in time gained during pregnancy at a signicance level of 5% and
power of 80%.
Statistical analysis was performed using 2 and Fisher exact tests for
qualitative variables and unpaired Student t test for quantitative vari-
ables. KaplanMeier survival analysis and log-rank test were used to
compare the 2 survival curves. P b 0.05 was considered to be statistically
signicant. SPSS version 20 (IBM, Armonk, NY, USA) was used for statis-
tical analysis.
3. Results
Ninety women with arrested preterm labor were recruited for the
study and randomized to group 1 (progesterone group; n = 45) or
group 2 (placebo group; n = 45). Two participants from group 1 and
3 from group 2 were lost to follow-up during the study period; their
data were analyzed via intention-to-treat analysis by replacing the
missing values with the means (Fig. 1).
The groups were matched with respect to age, parity, and presence
of risk factors for preterm birth. All clinical characteristics at recruit-
ment were matched between the groups. Mean gestational age at re-
cruitment was 31.91 weeks in group 1 and 32.42 weeks in group 2
(P = 0.20) (Table 1).
The mean latency period was signicantly longer in group 1
(33.29 22.16 vs 23.07 15.42 days; P = 0.013). There was a sig-
nicant difference in mean time to delivery between the groups; the
KaplanMeier plot depicted signicantly more undelivered women
in group 1 at each specic time point until delivery (P = 0.014;
log-rank 2 = 6.06; Fig. 2).
Mean gestational age at delivery was higher in group 1 (P = 0.07).
In group 1, most patients delivered at 37 weeks or later (28 [62%]),
while most patients in group 2 delivered at 3436 weeks (17 [38%])
(P = 0.01). There were signicantly fewer preterm births in group 1
than in group 2 (P = 0.03) (Table 2).

160 women with preterm labor received

nifedipine tocolysis
70 patients excluded (failure to arrest preterm labor, adverse
effects of nifedipine, rupture of membranes, obstetric/fetal
complications)

90 patients randomized to study groups

Group 1 (n=45) Group 2 (n=45)

Study group (progesterone) Placebo group

2 patients lost to follow-up 3 patients lost to follow-up

43 patients completed the study 42 patients completed the study

Fig. 1. Flow diagram of study participants.

Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after
arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
 M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxxxxx 3

Table 1 Table 2
Comparison of baseline characteristics between groups (n = 90).a Gestational age at delivery, number of preterm births, and readmission for preterm labor
(n = 90).a
Characteristics Group 1: progesterone Group 2: placebo P value
(n = 45) (n = 45) Outcome parameters Group 1: progesterone Group 2: placebo P value
(n = 45) (n = 45)
Age, y 24.11 2.386 23.71 2.928 0.479
Parity 0.994 Gestational age at delivery, wk 36.79 2.64 35.90 2.00 0.076
0 16 (36) 16 (36) 2831 + 6 2 (4) 0 (0) 0.014
1 22 (49) 21 (47) 3233 + 6 6 (13) 9 (20)
2 5 (11) 5 (11) 3436 + 6 7 (16) 17 (38)
History of previous preterm 6 (13) 2 (4) 0.265 37 28 (62) 16 (36)
birth Preterm birth, % 15 (33) 26 (58) 0.034
Presence of any risk factor 17 (38) 18 (40) N0.99 a
Values are given as mean SD or number (percentage) unless otherwise indicated.
for preterm birthb
Gestational age, wk 31.91 2.09 32.42 1.65 0.202
Cervical dilation, cm 1.67 0.36 1.65 0.33 0.784
Cervical effacement, % 55 19.96 49.00 17.85 0.136 progesterone with 200 mg of oral micronized progesterone and
Bishop score 4.18 1.07 4.02 1.09 0.484 400 mg of vaginal progesterone (30 vs 1734 ng/mL) [12]. The vaginal
a
Values are given as mean SD or number (percentage) unless otherwise indicated. route was not selected in the present study because it is associated with
b
History of preterm birth, rst-trimester abortion, second-trimester abortion, genito- vaginal irritation and unpleasant vaginal discharge [13]. The oral route
urinary infection, addiction. has better compliance.
In the present study, the mean latency period was signicantly
longer among women treated with progesterone compared with the
Mean birth weight was higher in group 1 than in group 2 (P = 0.009). placebo group. This is consistent with results from other studies
Most neonates in both groups were appropriate for gestational age, and [68]. A trial by Borna and Sahabi [6] showed signicant prolongation
there was no signicant difference in Apgar score at birth or 5 minutes of mean latency period with progesterone (36.1 17.9 days in pro-
between the groups (Table 3). The incidence of low birth weight neo- gesterone group vs 24.5 27.2 days in control group; P = 0.037). A
nates was signicantly lower in group 1 (P = 0.01). There were no randomized controlled trial by Sharami et al. [7] also showed that pro-
signicant differences between the groups with regard to neonatal gesterone therapy resulted in a longer latency period (23.88 18.01
ICU admission (P N 0.99), neonatal ICU stay (P = 0.60), respiratory vs 16.67 12.9 days; P = 0.004). In addition, Arikan et al. [8] found
distress syndrome (P = 0.77), sepsis (P = 0.67), or neonatal mortality that micronized progesterone treatment resulted in a longer latency
(P N 0.99). There was 1 (2.2%) neonatal death in each group. The cause period (32.1 17.8 vs 21.2 16.3 days; P b 0.05). The benecial
of death was severe prematurity with respiratory distress syndrome effect of oral micronized progesterone on prolongation of pregnancy
in group 1, and sepsis and pulmonary hemorrhage in group 2. Most was shown by the survival analysis in the present study, which
patients did not report any adverse effects; 4 women in each group depicted signicantly larger numbers of undelivered women in the
experienced headache, epigastric pain, and acne. progesterone group at each specic time point until delivery compared
Symptoms of preterm labor recurred in 46 patients; these women with placebo.
continued on the same medication and did not receive a different Prolongation of latency period with progesterone can be explained
therapy. by various mechanisms resulting in uterine quiescence. Progesterone
relaxes myometrial smooth muscle, blocks the action of oxytocin, in-
hibits the formation of gap junctions and prostaglandin synthesis, and
4. Discussion
has anti-inammatory properties [1417].
In the present study, mean gestational age at delivery was 1 week
In the present study, 200 mg of oral micronized progesterone
later in the progesterone group than in the placebo group, although
was used because of its adequate bioavailability and fewer adverse
this difference was not signicant. This is consistent with results from
effects compared with a 400-mg dose. The micronized form increases
the double-blind randomized controlled trial by Sharami et al. [7]. The
oral absorption and has comparable efcacy to that of vaginal progester-
one [11]. The literature reports comparable plasma concentrations of
Table 3
Neonatal outcome parameters at birth.a,b

Outcome parameters Group 1: progesterone Group 2: placebo P value

(n = 43) (n = 42)

Birth weight, kg 2.44 0.58 2.14 0.47 0.009

Appropriate for gestational age 40 (93) 42 (100) 0.241
Small for gestational age 2 (5) 0 (0)
Large for gestational age 1 (2) 0 (0)
Apgar score b7 at birth 4 (9) 1 (2) 0.360
Apgar score b7 at 5 minutes 1 (2) 0 (0) N0.99
Low birth weight 16 (37) 27 (64) 0.017
Respiratory distress syndrome 6 (14) 7 (17) 0.771
Sepsis 2 (5) 3 (7) 0.676
Hyperbilirubinemia 2 (5) 0 (0) 0.494
Otherc 1 (2) 2 (5) 0.616
NICU admission 10 (23) 9 (21) N0.99
Duration of NICU stay, d 4.70 3.72 5.89 4.25
Median (interquartile range) 4.0 (1.757.75) 4.0 (3.08.0) 0.604d
Neonatal mortality 1 (2) 1 (2) N0.99

Abbreviation: NICU, neonatal intensive care unit.

a
Values are given as mean SD or number (percentage) unless otherwise indicated.
b
Per-protocol analysis.
c
Fig. 2. KaplanMeier survival curve of time until delivery between the progesterone group Hypoglycemia, hypothermia, and hemorrhagic diseases of newborns.
d
and the placebo group. MannWhitney U test.

Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after
arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
4 M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxxxxx
2 other relevant randomized controlled trials [6,8]which were not
double-blindrevealed a signicant prolongation of gestational age at
delivery with progesterone.
The progesterone group had signicantly higher birth weight, signif-
icantly fewer preterm births, and signicantly fewer low birth weight
neonates. However, neonatal morbidity and mortality were similar be-
tween the groups. Lack of signicant improvement in neonatal outcome
could have been because the sample size was calculated to determine a
difference in latency period and, therefore, did not have sufcient
power to demonstrate a signicant difference in perinatal morbidity
and mortality. To account for this, future studies based on combined
sample size to detect maternal and neonatal outcome are needed. An-
other reason for similar neonatal outcome could have been that mean
gestational age at recruitment was relatively late (3132 weeks) and
most adverse neonatal outcomes are seen in earlier gestation (before
30 weeks); therefore, we may have missed signicant differences in
adverse perinatal outcome in extreme prematurity. Further studies fo-
cusing on women at less than 30 weeks of pregnancy and with larger
samples would provide valuable data on the use of oral micronized pro-
gesterone for maintenance tocolysis.
In conclusion, maintenance tocolysis with oral micronized proges-
terone signicantly prolonged pregnancy and decreased the number
of preterm births. The present results support the use of micronized
progesterone as a maintenance tocolytic for prolongation of pregnancy
in cases of arrested preterm labor.
Conict of interest
The authors have no conicts of interest.
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