# Abstract

 

## Background Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity. The withdrawal of progesterone, either actual or functional, is thought to be an antecedent to the onset of labour. There remains limited information on clinically relevant health outcomes as to whether vaginal progesterone may be of benefit for pregnant women with a history of a previous preterm birth, who are at high risk of a recurrence. Our primary aim was to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome in their infants, with secondary aims of examining the effects on other neonatal morbidities and maternal health and assessing the adverse effects of treatment. 

## Methods Women with a live singleton or twin pregnancy between 18 to \<24 weeks' gestation and a history of prior preterm birth at less than 37 weeks' gestation in the preceding pregnancy, where labour occurred spontaneously or in association with cervical incompetence or following preterm prelabour rupture of the membranes, were eligible. Women were recruited from 39 Australian, New Zealand, and Canadian maternity hospitals and assigned by randomisation to vaginal progesterone pessaries (equivalent to 100 mg vaginal progesterone) (*n* = 398) or placebo (*n* = 389). Participants and investigators were masked to the treatment allocation. The primary outcome was respiratory distress syndrome and severity. Secondary outcomes were other respiratory morbidities; other adverse neonatal outcomes; adverse outcomes for the woman, especially related to preterm birth; and side effects of progesterone treatment. Data were analysed for all the 787 women (100%) randomised and their 799 infants. 

## Findings Most women used their allocated study treatment (740 women, 94.0%), with median use similar for both study groups (51.0 days, interquartile range [IQR] 28.0--69.0, in the progesterone group versus 52.0 days, IQR 27.0--76.0, in the placebo group). The incidence of respiratory distress syndrome was similar in both study groups---10.5% (42/402) in the progesterone group and 10.6% (41/388) in the placebo group (adjusted relative risk [RR] 0.98, 95% confidence interval [CI] 0.64--1.49, *p* = 0.912)---as was the severity of any neonatal respiratory disease (adjusted treatment effect 1.02, 95% CI 0.69--1.53, *p* = 0.905). No differences were seen between study groups for other respiratory morbidities and adverse infant outcomes, including serious infant composite outcome (155/406 [38.2%] in the progesterone group and 152/393 [38.7%] in the placebo group, adjusted RR 0.98, 95% CI 0.82--1.17, *p* = 0.798). The proportion of infants born before 37 weeks' gestation was similar in both study groups (148/406 [36.5%] in the progesterone group and 146/393 [37.2%] in the placebo group, adjusted RR 0.97, 95% CI 0.81--1.17, *p* = 0.765). A similar proportion of women in both study groups had maternal morbidities, especially those related to preterm birth, or experienced side effects of treatment. In 9.9% (39/394) of the women in the progesterone group and 7.3% (28/382) of the women in the placebo group, treatment was stopped because of side effects (adjusted RR 1.35, 95% CI 0.85--2.15, *p* = 0.204). The main limitation of the study was that almost 9% of the women did not start the medication or forgot to use it 3 or more times a week. 

## Conclusions Our results do not support the use of vaginal progesterone pessaries in women with a history of a previous spontaneous preterm birth to reduce the risk of neonatal respiratory distress syndrome or other neonatal and maternal morbidities related to preterm birth. Individual participant data meta-analysis of the relevant trials may identify specific women for whom vaginal progesterone might be of benefit. 

## Trial registration Current Clinical Trials [ISRCTN20269066](#). # Results 

## Baseline information Of an estimated 1,919 eligible women able to be approached by the research team between February 2006 and September 2012, a total of 787 (41%) women consented to be enrolled in the study. Reasons for eligible women declining to participate included 'not interested in research' (25%), 'concerned about side effects and risks of use of drugs in pregnancy' (15%), 'no reason given' (13%), 'did not like the need to use vaginal pessaries' (9%), 'too busy' (8%), 'did not consider themselves to be at risk of preterm birth' (6%), 'partner declined to let them participate' (5), and 'other' (19%). Of the 787 women recruited, 398 (50.6%) were randomised to the progesterone group, and 389 (49.4%) to the placebo group. There were no losses to follow-up, with clinical outcomes to primary hospital discharge after birth available for all 787 (100%) women and their 799 infants ([Fig 1](#)). <figure> 10.1371/journal.pmed.1002390.g001 <p><img src="" /></p> <figcaption>Consolidated Standards of Reporting Trials (CONSORT) flow diagram of participants in the study.</figcaption> </figure> The 2 study groups were similar at the time of study entry for maternal demographics and key variables including gestational age, the reason for the preterm birth in the preceding pregnancy, and the gestational age at which that birth occurred ([Table 1](#)). The majority of participants had a singleton pregnancy, with less than 2% having a twin pregnancy ([Table 1](#)). Almost all women recruited in both study groups used their allocated study treatment (381 [95.7%] in the progesterone group and 359 [92.3%] in the placebo group), with similar median days of use in both study groups (51.0 days [interquartile range (IQR) 28.0--69.0] in the progesterone group versus 52.0 days [IQR 27.0--76.0] in the placebo group) ([Table 1](#)). ::::table-wrap

10.1371/journal.pmed.1002390.t001

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##

##

## Comparability of randomised study groups at trial entry and use of study treatment.

:::

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Characteristic Progesterone (*n* = 398) Placebo (*n* = 389)

______________________________________________________________________

Maternal age (years)[\*](#) 30.3 (5.5) 30.3 (5.6)
Public patient 343 (86.2) 347 (89.2)
Ethnicity[^‡^](#)\
White 286 (71.9) 289 (74.3)
Asian 43 (10.8) 41 (10.5)
Aboriginal or Torres Strait Islanders 8 (2.0) 3 (0.8)
Polynesian 8 (2.0) 8 (2.1)
Maori 10 (2.5) 10 (2.6)
Other 43 (10.9) 38 (9.8)
BMI category\
Underweight 16 (4.0) 18 (4.6)
Normal 156 (39.2) 147 (37.8)
Overweight 94 (23.6) 93 (23.9)
Obese 100 (25.1) 93 (23.9)
Unknown 32 (8.0) 38 (9.8)
Progesterone use < 16 weeks' gestation 14 (3.5) 12 (3.1)
Gestational age at randomization (weeks)[^#^](#) 20.6 (19.3, 22.1) 20.4 (19.3, 22.0)
Main reason for previous preterm birth\
Preterm labour 256 (64.3) 235 (60.4)
PPROM 127 (31.9) 140 (36.0)
Other 15 (3.8) 14 (3.6)
Gestational age of previous preterm birth\
\<28 weeks' 124 (31.2) 118 (30.3)
28 to \<34 weeks' 133 (33.4) 128 (32.9)
≥34 weeks' 141 (35.4) 143 (36.8)
Current pregnancy\
Singleton 390 (98.0) 385 (99.0)
Twins 8 (2.0) 4 (1.0)
Study treatment used 381 (95.7) 359 (92.3)
Study treatment taken (days)[^#^](#) 51.0 (28.0, 69.0) 52.0 (27.0, 76.0)

Values are number (percentage), unless otherwise indicated. BMI, body
mass index; CI, confidence interval; PPROM, preterm prelabour rupture of
membranes.

- Values are means (standard deviation).

^‡^ Ethnicity as reported by the participant.

^#^ Values are medians (interquartile range).:::: 

## Primary infant outcomes 

### Risk of respiratory distress syndrome and severity of respiratory disease The risk of respiratory distress syndrome was similar in both study groups, 10.5% (42/402) in the progesterone group and 10.6% (41/388) in the placebo group (adjusted RR 0.98, 95% CI 0.64--1.49, *p* = 0.912), as was the severity of any neonatal respiratory disease (adjusted treatment effect 1.02 \[95% CI 0.69--1.53, *p* = 0.905\]) ([Table 2](#)). Unadjusted analyses showed similar findings to the analyses adjusted for gestational age at randomisation, gestation of previous preterm birth, and reason for previous preterm birth ([Table 2](#)). ::::table-wrap
10.1371/journal.pmed.1002390.t002

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##

##

## Primary and secondary neonatal outcomes by study group.

:::

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Outcome Progesterone *n* = 406 Placebo *n* = 393 Unadjusted Treatment Effect for Progesterone versus Placebo (95% CI) Unadjusted *p*-Value Adjusted Treatment Effect for Progesterone versus Placebo (95% CI) Adjusted *p*-Value[^#^](#)

______________________________________________________________________

*Primary Outcomes*\
Neonatal RDS 42/402 (10.5) 41/388 (10.6) 0.99 (0.65--1.51) 0.958 0.98 (0.64--1.49) 0.912
Severity of respiratory disease[\*](#) 1.03 (0.69--1.53) 0.883 1.02 (0.69--1.53) 0.905
Nil 338/402 (84.1) 327/388 (84.3)\
Mild 24/402 (6.0) 28/388 (7.2)\
Moderate 32/402 (8.0) 26/388 (6.7)\
Severe 8/402 (2.0) 7/388 (1.8)\
*Secondary Outcomes*\
*Other Respiratory Measures*\
Oxygen therapy 43/402 (10.7) 45/388 (11.6) 0.92 (0.61--1.38) 0.696 0.92 (0.62--1.37) 0.670
Duration of oxygen therapy[\*\*](#) 4.96 (38.0) 5.43 (45.7) 0.91 (0.29--2.84) 0.875 0.85 (0.32--2.29) 0.751
Highest FiO~2~ at \<12 hours of birth[^‡^](#) 29.6 (13.9) 27.9 (13.0) 1.68 (−3.03 to 6.38) 0.485 1.37 (−2.97 to 5.71) 0.536
Mechanical ventilation 26/402 (6.5) 23/388 (5.9) 1.09 (0.62--1.92) 0.763 1.08 (0.62--1.89) 0.788
Duration of mechanical ventilation (days)[\*\*](#) 0.50 (3.0) 0.70 (4.8) 0.72 (0.29--1.79) 0.477 0.51 (0.21--1.24) 0.137
Surfactant used 26/402 (6.5) 25/388 (6.4) 1.00 (0.58--1.74) 0.989 0.99 (0.58--1.72) 0.984
Nitric oxide for respiratory support 0/402 (0.0) 3/388 (0.8) N/A 0.118[^](#) N/A N/A
Air leak syndrome 2/402 (0.5) 1/388 (0.3) N/A 1.000[^](#) N/A N/A
Chronic lung disease 10/402 (2.5) 7/388 (1.8) 1.38 (0.49--3.87) 0.542 N/A N/A
*Adverse Infant Outcomes*\
Serious infant outcome (composite) 155/406 (38.2) 152/393 (38.7) 0.99 (0.82--1.18) 0.887 0.98 (0.82--1.17) 0.798
Preterm birth at \<37 weeks' gestation 148/406 (36.5) 146/393 (37.2) 0.98 (0.81--1.18) 0.842 0.97 (0.81--1.17) 0.765
Perinatal mortality 5/406 (1.2) 7/393 (1.8) 0.69 (0.22--2.16) 0.526 N/A N/A
Stillbirth 4/406 (1.0) 5/393 (1.3) N/A 0.749[^](#) N/A N/A
Infant death 1/406 (0.3) 2/393 (0.5) N/A 0.619[^](#) N/A N/A
Born by caesarean section 126/406 (31.0) 105/393 (26.7) 1.16 (0.93--1.45) 0.187 1.17 (0.94--1.46) 0.160
Apgar score < 4 at 5 minutes 6/406 (1.5) 6/393 (1.5) 0.97 (0.31--2.98) 0.955 N/A N/A
Birth weight (g) [^‡^](#) 2870.2 (849.2) 2926.5 (794.2) −56.3 (−174.9 to 62.4) 0.353 −53.6 (−171.7 to 64.4) 0.373
Birth weight z-score[^‡^](#) 0.13 (1.1) 0.20 (1.0) −0.07 (−0.22 to 0.07) 0.333 −0.07 (−0.21 to 0.08) 0.356
Birth weight < 3rd centile 8/402 (2.0) 7/388 (1.8) 1.10 (0.38--3.19) 0.856 N/A N/A
Any IVH 9/402 (2.2) 9/388 (2.3) 0.97 (0.39--2.41) 0.939 N/A N/A
Grade 3/4 IVH 1/402 (0.3) 1/388 (0.3) N/A 1.000[^](#) N/A N/A
Periventricular leucomalacia 0/402 (0.0) 1/388 (0.3) N/A 0.491[^](#) N/A N/A
Inotropic support for PDA 11/402 (2.7) 9/388 (2.3) 1.18 (0.47--2.96) 0.725 N/A N/A
Necrotising enterocolitis 2/402 (0.5) 2/388 (0.5) N/A 1.000[^](#) N/A N/A
Proven early neonatal sepsis 0/402 (0.0) 2/388 (0.5) N/A 0.241[^](#) N/A N/A
Retinopathy of prematurity 12/401 (3.0) 9/386 (2.3) 1.28 (0.51--3.26) 0.600 N/A N/A
Admission to NICU 68/402 (16.9 71/388 (18.3) 0.92 (0.68--1.27) 0.624 0.92 (0.67--1.25) 0.591
Infant postnatal length of stay (days)[\*\*](#) 11.93 (21.1) 11.24 (21.6) 1.06 (0.80--1.41) 0.677 1.06 (0.79--1.41) 0.717

Denominators are 406 in the progesterone group and 393 in the placebo
group for outcomes that include all infants alive at the time of
randomisation and 402 and 388, respectively, for outcomes relating to
only live-born infants (where the 4 stillbirths in the progesterone
group and 5 stillbirths in the placebo group are not included). Values
are number (percentage), and treatment effects are relative risks unless
otherwise indicated. Abbreviations: CI, confidence interval; FIO~2~,
fractional inspired oxygen; GA, gestational age; IVH, intraventricular
haemorrhage; N/A, not available; NICU, neonatal intensive care unit;
PDA, patent ductus arteriosus; RDS, respiratory distress syndrome.

^#^ Adjusted for GA at randomization, GA of previous preterm birth, and
reason for previous preterm birth.

- Values are number (percentage), and treatment effects are odds ratios
  of higher severity.

\*\* Values are mean (standard deviation), and treatment effects are
ratios of means.

^‡^ Values are mean (standard deviation), and treatment effects are
differences in means.

^ *p*-Value from Fisher's exact test.:::: 

## Secondary outcomes for the infant 

### Other respiratory measures In keeping with these findings, there were no differences between the study groups for any of the secondary respiratory outcomes that included need for and duration of oxygen therapy, maximum appropriate FIO~2~ values within 12 hours of birth, use and duration of mechanical ventilation, use of surfactant, use of nitric oxide, air leak syndrome, and chronic lung disease ([Table 2](#)). 

### Adverse infant outcomes Overall, the risk of any serious adverse outcome for the infant was similar between the study groups (155/406 [38.2%] in the progesterone group and 152/393 [38.7%] in the placebo group, adjusted RR 0.98, 95% CI 0.82--1.17, *p* = 0.798) ([Table 2](#)). There were 12 (1.5%) infant deaths before hospital discharge: 4 stillbirths and 1 death of a live-born infant in the progesterone group and 5 stillbirths and 2 deaths of live-born infants in the placebo group---not a significant difference ([Table 2](#)). The proportion of infants born before 37 weeks' gestation was similar in both study groups (148/406 [36.5%] in the progesterone group and 146/393 [37.2%] in the placebo group, adjusted RR 0.97, 95% CI 0.81--1.17, *p* = 0.765). A similar proportion of infants were born by caesarean section in both study groups. No differences were evident between the study groups for any of the other individual adverse infant outcomes that included low Apgar score, small for gestational age at birth, intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus requiring treatment, necrotising enterocolitis, proven early neonatal sepsis, retinopathy of prematurity, and need for admission to the neonatal intensive care unit and duration of the infant's postnatal stay ([Table 2](#)). 

## Secondary outcomes for the women 

### Significant health outcomes There were no differences between study groups in the proportion of women experiencing 1 or more significant health outcomes overall (180/398 [45.2%] in the progesterone group and 174/389 [44.7%] in the placebo group, adjusted RR 1.00, 95% CI 0.86--1.17, *p* = 0.994) or in the individual health outcomes, particularly those related to preterm birth, including use of tocolytic therapy and antenatal corticosteroids prior to the birth, antepartum haemorrhage, preeclampsia, risk of rupture of the membranes preterm or at or near term, chorioamnionitis requiring antibiotics, and postpartum haemorrhage ([Table 3](#)). There were no maternal deaths. Antibiotic use after birth was similar between the study groups, as was the need for antenatal admission and the length of any antenatal or postnatal hospital stay ([Table 3](#)). ::::table-wrap
10.1371/journal.pmed.1002390.t003

::: caption



##

##

## Secondary maternal outcomes by study group, including those related to preterm birth, psychological health, side effects of study treatment, and compliance.

:::

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Outcome Progesterone (*n* = 398) Placebo (*n* = 389) Unadjusted Treatment Effect for Progesterone versus Placebo (95% CI) Unadjusted *p*-Value Adjusted Treatment Effect for Progesterone versus Placebo (95% CI) Adjusted *p*-Value[^#^](#)

______________________________________________________________________

*Significant Health Outcomes*\
Serious maternal outcome 180/398 (45.2) 174/389 (44.7) 1.01 (0.87--1.18) 0.889 1.00 (0.86--1.17) 0.994
Tocolytic therapy 71/398 (17.8) 77/389 (19.8) 0.90 (0.67--1.21) 0.483 0.90 (0.68--1.20) 0.478
Antenatal corticosteroid treatment 147/398 (36.9) 143/389 (36.8) 1.00 (0.84--1.21) 0.960 1.01 (0.84--1.21) 0.926
Antepartum haemorrhage 17/398 (4.3) 20/389 (5.1) 0.83 (0.44--1.56) 0.565 0.83 (0.44--1.56) 0.561
Pre-eclampsia 12/398 (3.0) 8/389 (2.1) 1.47 (0.61--3.55) 0.396 N/A N/A
Preterm prelabour rupture of membranes 51/398 (12.8) 44/389 (11.3) 1.13 (0.78--1.65) 0.518 1.14 (0.78--1.66) 0.500
Term prelabour rupture of membranes 24/398 (6.0) 25/389 (6.4) 0.94 (0.55--1.61) 0.818 0.92 (0.54--1.58) 0.772
Chorioamnionitis requiring antibiotics 19/398 (4.8) 13/389 (3.3) 1.43 (0.72--2.85) 0.312 1.49 (0.75--2.98) 0.253
Postpartum haemorrhage ≥ 500 ml 88/398 (22.1) 91/389 (23.4) 0.95 (0.73--1.22) 0.668 0.95 (0.73--1.22) 0.682
Postnatal antibiotic use 43/398 (10.8) 33/389 (8.5) 1.27 (0.83--1.96) 0.272 1.29 (0.84--1.98) 0.247
Antenatal hospitalization 191/398 (48.0) 186/389 (47.8) 1.00 (0.87--1.16) 0.961 1.01 (0.88--1.16) 0.908
Length of antenatal hospitalization (days)[\*\*](#) 3.82 (10.6) 3.46 (7.8) 1.10 (0.82--1.49) 0.523 1.02 (0.76--1.37) 0.919
Length of postnatal hospitalization (days)\*\* 2.72 (2.1) 2.60 (1.9) 1.05 (0.95--1.16) 0.346 1.05 (0.95--1.15) 0.351
*Psychological Health at 34 Weeks'*[^

##^](#)\
Quality of life (SF-36) domains\
Physical functioning[\*](#) 54.04 (26.3) 55.81 (27.1) −1.77 (−6.30 to 2.77) 0.445 −1.30 (−5.77 to 3.18) 0.570
Physical role[\*](#) 38.35 (40.7) 44.91 (41.5) −6.56 (−13.54 to 0.42) 0.066 −6.62 (−13.55 to 0.32) 0.061
Bodily pain[\*](#) 59.60 (22.7) 59.90 (24.8) −0.30 (−4.33 to 3.73) 0.884 −0.52 (−4.53 to 3.49) 0.799
General health[\*](#) 76.61 (17.8) 75.08 (17.8) 1.53 (−1.50 to 4.55) 0.323 1.47 (−1.56 to 4.50) 0.342
Vitality[\*](#) 49.44 (20.0) 50.45 (20.5) −1.02 (−4.46 to 2.42) 0.562 −1.06 (−4.51 to 2.38) 0.546
Social functioning[\*](#) 69.55 (27.0) 73.35 (25.7) −3.80 (−8.28 to 0.67) 0.096 −3.76 (−8.22 to 0.69) 0.098
Emotional role[\*](#) 82.21 (32.3) 82.52 (33.6) −0.31 (−5.90 to 5.28) 0.913 −0.21 (−5.78 to 5.36) 0.941
Mental health[\*](#) 76.92 (17.9) 77.24 (16.2) −0.33 (−3.23 to 2.58) 0.827 −0.27 (−3.16 to 2.61) 0.853
Overall physical component[\*](#) 37.43 (9.8) 38.32 (10.6) −0.90 (−2.63 to 0.84) 0.312 −0.85 (−2.58 to 0.87) 0.333
Overall mental component[\*](#) 51.95 (10.4) 52.23 (9.4) −0.28 (−1.97 to 1.40) 0.743 −0.30 (−1.98 to 1.38) 0.724
Anxiety (STAI score)[\*](#) 10.91 (3.9) 11.02 (3.7) −0.11 (−0.75 to 0.53) 0.739 −0.10 (−0.74 to 0.54) 0.763
Depression (EPDS score > 12) 25/266 (9.4) 24/266 (9.0) 1.04 (0.61--1.78) 0.881 1.05 (0.62--1.78) 0.868
*Side Effects of Therapy and Compliance*\
Women reporting side effects 134/394 (34.0) 118/382 (30.9) 1.10 (0.90--1.35) 0.354 1.11 (0.90--1.36) 0.322
Side effects reported\
Headache 39/394 (9.9) 35/382 (9.2) 1.08 (0.70--1.67) 0.727 1.07 (0.69--1.65) 0.769
Nausea 33/394 (8.4) 24/382 (6.3) 1.33 (0.80--2.21) 0.266 1.33 (0.80--2.21) 0.269
Pain or discomfort 29/394 (7.4) 29/382 (7.6) 0.97 (0.59--1.59) 0.903 0.96 (0.59--1.56) 0.861
Breast tenderness 12/394 (3.1) 16/382 (4.2) 0.73 (0.35--1.52) 0.396 0.72 (0.34--1.49) 0.372
Coughing 10/394 (2.5) 5/382 (1.3) 1.94 (0.67--5.62) 0.223 N/A N/A
Other 66/394 (16.8) 58/382 (15.2) 1.10 (0.80--1.52) 0.552 1.13 (0.82--1.55) 0.469
Treatment stopped because of side effects 39/394 (9.9) 28/382 (7.3) 1.35 (0.85--2.15) 0.205 1.35 (0.85--2.15) 0.204
Noncompliant with treatment (did not start treatment or forgot to use ≥ 3 times a week) 33/394 (8.4) 35/380 (9.2) 0.91 (0.58--1.43) 0.682 0.93 (0.59--1.46) 0.743
Did not start treatment or stopped before 34 weeks' gestation 131/381 (34.4) 113/360 (31.4) 1.10 (0.89--1.35) 0.3867 1.08 (0.88--1.33) 0.454

Values are number (%), and treatment effects are relative risks unless
otherwise indicated. Term prelabour rupture of membranes was adjusted
for gestational age at randomisation and gestational age of previous
preterm birth only. Experienced side effects: headache and nausea were
adjusted for gestational age at randomisation and gestational age of
previous preterm birth only. Abbreviations: CI, confidence interval;
EPDS, Edinburgh Postnatal Depression Scale \[[25](#)\]; SF-36, 36-Item
Short Form Health Survey \[[23](#)\]; STAI, State-Trait Anxiety
Inventory \[[24](#)\].

# Adjusted for gestational age at randomisation, gestational age of

previous preterm birth, and reason for previous preterm birth.



## The denominators are 266 for progesterone and 265 for placebo.

- Values are mean (standard deviation), and treatment effects are
  differences in means.

\*\* Values are mean (standard deviation), and treatment effects are
ratios of means.:::: 

### Psychological health All measures on the 36-Item Short Form Health Survey (SF-36), including the overall physical and mental components, were similar in both study groups. No differences were seen in the proportion of women with a score on the Edinburgh Postnatal Depression Scale (EPDS) that was suggestive of depression (9.4% in the progesterone group and 9.0% in the placebo group), and the level of anxiety was similar in the 2 study groups ([Table 3](#)). 

### Side effects of study treatment and compliance The proportion of women reporting any side effects of the treatment at 34 weeks' gestation was similar between the study groups (134/394 [34.0%] in the progesterone group versus 118/382 [30.9%] in the placebo group), as was the proportion of women who stopped therapy because of side effects (39/394 [9.9%] in the progesterone group versus 28/382 [7.3%] in the placebo group) ([Table 3](#)). A similar proportion of women in both study groups either did not start the medication or forgot to use it 3 or more times a week, our measure of compliance (33/394 [8.4%] in the progesterone group and 35/380 [9.2%] in the placebo group) ([Table 3](#)). A similar proportion of women in both study groups used the study treatment up to 34 weeks' gestation and remained undelivered (250/381 [65.6%] in the progesterone group versus 247/360 [68.6%] in the placebo group).


Extracted trial result:
Outcome: adverse infant outcomes, including serious infant composite outcome (binary)
Intervention: vaginal progesterone pessaries (equivalent to 100 mg vaginal progesterone)
Comparator: placebo
Intervention events: 155
Intervention group size: 406
Comparator events: 152
Comparator group size: 393