BMJ · Confidential: For Review Only Induction of labour at 41 weeks versus expectant management until 42 weeks (the Swedish postterm induction study - SWEPIS), a multicentre, open

Confidential: For Review OnlyInduction of labour at 41 weeks versus expectant

management until 42 weeks (the Swedish postterm induction study - SWEPIS), a multicentre, open label,

randomised, superiority trial

Journal: BMJ

Manuscript ID BMJ-2019-051538.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 18-Sep-2019

Complete List of Authors: Wennerholm, Ulla-Britt; Sahlgrenska University Hospital, Department of Obstetrics and gynecology; Sahlgrenska Academy, Institute of Clinical SciencesSaltvedt, Sissel; Karolinska Institutet, Women's and Children's Health; Karolinska University Hospital, Obstetrics and Gynaecology UnitWessberg, Anna; Sahlgrenska Academy, Instittute of Health and Care SciencesAlkmark, Mårten; Sahlgrenska University Hospital, Department of Obstetrics and gynecology; Sahlgrenska Academy, Institute of Clinical SciencesBergh, Christina; Sahlgrenska University Hospital, Department of Obstetrics and gynecology; Sahlgrenska Academy, Institute of Clinical SciencesBrismar Wendel, Sophia; Karolinska Institute, Department of Clinical SciencesFadl, Helena; University Örebro, School of medical Health and sciences, Obstetrics and GynecologyJonsson, Maria; Uppsala University, Department of Women's and Children's HealthLadfors, Lars; Sahlgrenska University Hospital, Department of Obstetrics and gynecology; Sahlgrenska Academy, Instiutet of Clinical SciencesSengpiel, Verena; Clinical Science, Obstetrics and Gynecology, The Sahlgrenska Academy, Sahlgrenska University Hospital, GothenburgWesstrom, Jan; Uppsala University, Center for Clinical Research DalarnaWennergren, Göran; Sahlgrenska University Hospital, Department of Paediatrics; Sahlgrenska Academy, Institute of Clinical SciencesWikström, Anna-Karin; Uppsala University, Department of Women's and Children's HealthElden, Helen; Sahlgrenska Academy, Instittute of Health and Care SciencesStephansson, Olof; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Medicine, SolnaHagberg, Henrik; Sahlgrenska University Hospital, Department of Obstetrics and Gynecology; Sahlgrenska Academy, Institute of Clinical Sciences

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review OnlyKeywords: induction, late-term pregnancy, perinatal mortality, perinatal morbidity,

post-term pregnancy, term-pregnancy

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Confidential: For Review Only

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1 Induction of labour at 41 weeks versus expectant management until 42 weeks (the 2 Swedish postterm induction study - SWEPIS), a multicentre, open label, randomised, 3 superiority trial

4 Ulla-Britt Wennerholm1*#, Sissel Saltvedt2*, Anna Wessberg3, Mårten Alkmark1, Christina 5 Bergh1, Sophia Brismar Wendel4, Helena Fadl5, Maria Jonsson6, Lars Ladfors1, Verena 6 Sengpiel1, Jan Wesström7, Göran Wennergren8, Anna-Karin Wikström6, Helen Elden3**, 7 Olof Stephansson9**, Henrik Hagberg1**

8 *shared first authorship; **shared senior authorship; #corresponding author

9 1Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska

10 Academy, Gothenburg University, Sahlgrenska University Hospital, Gothenburg, Sweden

11

12 2Department of Women’s and Children’s health, Karolinska Institutet, Karolinska University

13 Hospital, Stockholm, Sweden

14 3Institute of Health and Care Sciences, Sahlgrenska Academy, Gothenburg University,

15 Sweden

16 4Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm,

17 Sweden

18 5Department of Obstetrics and Gynecology, Faculty of Medicine and Health, Örebro

19 University, Örebro, Sweden

20

21 6Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

22 7Center for Clinical Research Dalarna, Uppsala University, Sweden

23 8Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg

24 University, Sahlgrenska University Hospital, Gothenburg, Sweden

25 9Department of Medicine, Solna, Clinical Epidemiology Division, Karolinska Institutet,

26 Stockholm, Sweden

27 Correspondence to:

28 Ulla-Britt Wennerholm

29 Dep Obstetrics, Institute of Clinical Sciences, Sahlgrenska Hospital East

30 416 85 Göteborg, Sweden

31 [email protected]

32

33

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34 Abstract

35 Objective

36 To evaluate if induction of labour at 41 weeks compared with expectant management and

37 induction of labour at 42 weeks may improve perinatal and maternal outcomes in low risk

38 women.

39 Design

40 Multicentre, open label, randomised controlled superiority trial.

41 Setting

42 Fourteen hospitals in Sweden, 2016-2018.

43 Participants

44 2760 low risk women with an uncomplicated singleton pregnancy were randomised (1:1) by

45 the Swedish Pregnancy Register.

46 Interventions

47 Induction of labour at 41 weeks (induction group, n=1381), or expectant management until

48 induction of labour at 42 weeks (expectant management group, n=1379).

49 Main outcome measures

50 The primary outcome was a composite perinatal outcome including one or more of the

51 following: stillbirth, neonatal mortality, Apgar score <7 at 5 minutes, pH<7.00 or metabolic

52 acidosis (pH <7.05 and base deficit >12 mmol/l) in the umbilical artery, hypoxic ischaemic

53 encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome,

54 mechanical ventilation within 72 hours, and/or obstetric brachial plexus injury. Primary

55 analysis was by intention to treat.

56 Results

57 The study was stopped early owing to a significantly higher rate of perinatal mortality in the

58 expectant management group. There was no difference in the composite primary perinatal

59 outcome between the induction group 2.4% (33/1381) and expectant management group 2.3%

60 (31/1379) (Relative Risk [RR] 1.06; 95% confidence interval [CI] 0.65 to 1.73), p=0.90).

61 There were no perinatal deaths in the induction group and six perinatal deaths (five stillbirths

62 and one early neonatal death) in the expectant management group (p=0.031). The proportion

63 of caesarean delivery, instrumental vaginal delivery or any major maternal morbidity did not

64 differ between the groups.

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65 Conclusions .

66 Induction of labour at 41 weeks versus expectant management until 42 weeks does not alter

67 the composite perinatal outcome, the primary outcome of this study. However, a reduction of

68 the secondary outcome perinatal mortality is observed without increasing adverse maternal

69 outcome. Although these results should be interpreted cautiously, labour induction ought to be

70 offered women no later than at 41+0 weeks and could be one (of few) interventions that

71 reduces stillbirth.

72

73 Trial registration

74 This trial is registered in Current Controlled Trials, ISRCTN26113652.

75

76 Keywords Induction, late-term pregnancy, perinatal mortality, perinatal morbidity, post-term

77 pregnancy, term-pregnancy

78

79 What is already known on this topic

80 Meta-analyses comparing induction of labour at or beyond term with expectant management

81 have shown a generally improved perinatal outcome with induction. It is not known if

82 induction at 41 weeks results in a better outcome compared to expectancy and induction at 42

83 weeks.

84

85 What this study adds

86 We showed that induction of labour at 41 full weeks in low risk pregnancies is associated

87 with a decreased risk of perinatal mortality compared with expectant management with

88 induction of labour at 42 full weeks. Other neonatal outcomes or caesarean delivery did not

89 differ between groups. Women with low risk pregnancies should be informed of the risk

90 profile of induction of labour versus expectant management and offered induction of labour

91 no later than at 41 full weeks.

92

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93 Introduction

94 Adverse perinatal outcomes gradually increase after 40 weeks and are significantly elevated

95 postterm (≥42 weeks [≥294 days]).1-2 The risk of stillbirth has been shown to increase after

96 term,1-5 and worldwide as much as 14% of stillbirth is associated with prolonged pregnancy.2

97 Furthermore, maternal complications also increase with duration of pregnancy after 40

98 weeks.1 To date, there is no agreement on how to manage late term (41+0 to 42+0 weeks)

99 pregnancies. The World Health Organisation (WHO) recommends induction of labour at

100 41+0 weeks6 and many countries offer induction of labour between 41+0 and 42+0 weeks to

101 avoid prolonged pregnancy.7,8

102 Randomised controlled trials (RCT) have compared induction of labour with expectant

103 management in prolonged pregnancies, most of them with inconclusive results with respect to

104 perinatal mortality and major morbidity.9 The results from the latest Cochrane review from

105 2018 showed lower rates of caesarean delivery and perinatal death but a higher rate of

106 operative vaginal delivery in the induction group compared with the expectant management

107 group.9 After the latest Cochrane review and after the initiation of the present study10, two

108 large RCTs examining low risk pregnancies have been published. A large trial from the US,

109 the ARRIVE trial, compared induction of labour in nulliparous women at 39+0 to 39+4 weeks

110 with expectant management until 41+0 weeks.11 No significant difference was found in

111 perinatal outcome between groups while the frequency of caesarean delivery was significantly

112 lower in the early induction group. Another large recent trial from the Netherlands, the

113 INDEX trial, compared induction of labour at 41+0 to 41+1 weeks to expectant management

114 until 42+0 weeks.12 The results could not confirm non-inferiority for adverse perinatal

115 outcome of expectant management, instead a significantly higher risk of adverse perinatal

116 outcome was found in the expectant management group. No significant difference in the rate

117 of caesarean delivery was found.

118 The current practice in many centres in United Kingdom and Scandinavia is to induce

119 delivery no later than at 42 weeks but several studies suggests that the risk of perinatal

120 mortality and morbidity actually increases significantly already at 41 weeks.3-5 There may be

121 a slightly increased risk of stillbirth already at 39 weeks of gestation and a gradual

122 exponential rise in risk as the pregnancy proceeds and approaches 42 weeks13 being

123 significant in most studies at 41 weeks3-5 whereas the risk of neonatal mortality is not

124 increased until 41 weeks.3,13 Therefore, we found it clinically justified to compare induction at

125 41 weeks with 42 weeks of gestation with respect to maternal and perinatal outcomes. At the

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126 start of the present trial, only two studies (one was an abstract) out of 30 included in the

127 Cochrane review (above) specifically compared induction of labour at 41 weeks with

128 expectant management until 42 weeks.14,15

129 The objective of this study was to evaluate if induction of labour at 41+0-2 weeks compared

130 with expectant management until induction of labour at 42+0-1 weeks was superior in terms

131 of perinatal outcome in healthy women with a low risk pregnancy.

132

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134 Methods

135 Study design

136 SWEPIS (SWEdish Post term Induction Study) was a multicentre, open label, randomised

137 controlled superiority trial conducted in Sweden from May 2016 to October, 2018. The trial

138 was register-based, meaning that randomisation and most data collection was done by using

139 the Swedish Pregnancy Register16 In all, 14 hospitals with linked antenatal clinics were

140 involved in the trial. Of the hospitals, four were university clinics and nine were county

141 hospitals comprising about 60 000 deliveries/year of the around 115 000 to 120 000

142 deliveries/year in Sweden. The trial was conducted according to the CONSORT guidelines

143 and was registered in Current Controlled Trials (ISRCTN26113652, the protocol being

144 available online (https://www-ncbi-nlm-nih-gov.proxy.kib.ki.se/pubmed/26951777) and as a

145 publication.10 The trial was undertaken within the Swedish Network for National Clinical

146 Studies within Obstetrics and Gynaecology (SNAKS).

147

148 Participants

149 Pregnant women were eligible for participation if: age ≥18 years; capable of understanding

150 oral and written information; singleton pregnancy with a fetus in cephalic presentation at

151 40+6 to 41+1 weeks according to ultrasound-based dating in first or early second trimester.

152 Exclusion criteria were: previous caesarean delivery or other uterine surgery, pre-gestational

153 and insulin dependent gestational diabetes, hypertensive disorder of pregnancy, known

154 oligohydramnios (amniotic fluid index <50 mm or deepest vertical pocket <20 mm) or small

155 for gestational age fetus (estimated fetal weight <-2 standard deviations (SD) according to the

156 sex and gestational age specific Swedish reference),17 diagnosed fetal malformation,

157 contraindication to vaginal delivery, any other maternal condition hindering the pregnancy to

158 proceed to 42 weeks.

159 Study logistics

160 General information about the study was given by posters or videos in the waiting rooms at

161 the antenatal clinics and by advertising in local daily newspapers. More detailed information

162 was provided on the study web site. At around 40 weeks, oral information about the study was

163 given by the midwife in Swedish or written information in any of 17 immigrant languages. In

164 the Stockholm region (five clinics), women were enrolled in association with a 41-week

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165 ultrasound scan which is offered to all pregnant women in the region. This is a voluntary scan

166 with almost 100% coverage aiming to confirm a normal pregnancy (defined as mean fetal

167 abdominal diameter >110 mm and normal amniotic fluid) before proceeding to 42 weeks. The

168 ultrasound midwife answered questions about the study and handled the randomisation after

169 written informed consent was obtained. In all other centres, women interested in taking part

170 were invited to a visit with a research midwife who managed patient consent and

171 randomisation. Outside the Stockholm region, 41-week scans were not routinely offered.

172

173 Randomisation and masking

174 Randomisation was done between 40+6 and 41+1 weeks. Enrolled women were allocated to

175 the intervention group (induction) or the control group (expectant management group). In the

176 induction group, labour was induced within 24 hours of randomisation (i. e. the same or the

177 next day) but not earlier than 41+0 weeks. In the expectant management group, labour was

178 induced at 42+0 to 42+1 weeks.

179 Allocation to either trial group, 1:1 was done with central on-line randomisation by dynamic

180 allocation with centre and parity (primiparity versus multiparity) as minimisation variables.

181 The Swedish Pregnancy Register16 set up the randomisation module which was incorporated

182 in the register but separate from the register data. Access to the randomisation module used a

183 separate log-in system. The module also included an electronic Case Report Form. After

184 delivery and the neonatal period, data on antenatal, delivery and neonatal characteristics were

185 retrieved from the Swedish Pregnancy Register and Swedish Neonatal Quality Register18

186 using the unique personal identification number. Because the majority of variables in the

187 study were included in the quality registers, the study could be performed relatively fast and

188 at a low cost.

189 Due to the nature of the intervention, blinding was not possible for participants or caregivers.

190

191 Strategies

192 Induction of labour was carried out in the same way in both groups. At admission, all women

193 were examined regarding blood pressure, proteinuria, fetal presentation by abdominal

194 palpation, cervical status, and fetal wellbeing by cardiotocography (CTG). In case of a well

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195 engaged fetal head and a ripe cervix (Bishop score ≥6 for primiparas and ≥5 for multiparas)

196 amniotomy was performed, followed by oxytocin infusion after 1-2 hours without

197 spontaneous regular contractions. In case of an unengaged fetal head or a less ripe cervix, any

198 of the following methods was used, according to local routines: mechanical dilation with a

199 Foley-like catheter; oral misoprostol (Cytotec® or Angusta®); controlled released vaginal

200 misoprostol insert (Misodel®); prostaglandin E2 vaginally (Minprostin® gel or Propess®

201 vaginal insert).

202 After randomisation, no monitoring within the framework of the trial was offered. In Sweden,

203 most antenatal clinics offer one follow-up visit after term, usually around 41 weeks, including

204 measurement of blood pressure, fundal height and fetal heart rate by doptone. Further

205 examinations, induction of labour or caesarean delivery are initiated for usual obstetric

206 indications, such as decreased fetal movements, a suspicion of fetal growth restriction,

207 preeclampsia etc. After 41 weeks, the threshold for interventions is low. Indication for a

208 scheduled caesarean section included undiagnosed breech/transverse presentation with failed

209 external version. Fetal scalp blood sampling (pH or lactate) was performed during labour

210 when indicated.

211 Outcomes

212 Primary outcome was a composite perinatal outcome of perinatal mortality and morbidity.

213 Perinatal mortality was defined as stillbirth and neonatal death (day 0-27). Neonatal

214 morbidity was defined as one or more of the following outcomes: Apgar score at 5 minutes

215 <7, pH <7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/l in the umbilical

216 artery), hypoxic ischaemic encephalopathy (HIE) I-III, intracranial haemorrhage, convulsions,

217 meconium aspiration syndrome, mechanical ventilation within 72 hours, obstetric brachial

218 plexus injury.

219 Secondary neonatal outcomes were: the individual components of the primary perinatal

220 outcome, admission to neonatal intensive care unit (NICU), Apgar score <4 at 5 minutes,

221 birth weight, macrosomia (≥4500 g), neonatal jaundice, therapeutic hypothermia, pneumonia,

222 sepsis.

223 Secondary maternal outcomes were: use of epidural anaesthesia, caesarean delivery, operative

224 vaginal delivery, duration of labour (from onset of regular contractions to delivery of the

225 baby), chorioamnionitis, shoulder dystocia, perineal tear III-IV, postpartum haemorrhage

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226 (>1000 ml), wound infection, urinary tract infection, endometritis, sepsis, breastfeeding at

227 discharge from hospital, and at four weeks postpartum.

228 Exploratory neonatal outcomes were: neonatal hypoglycaemia, birth trauma (fracture of long

229 bone, clavicle or skull, other neurologic injury, retinal haemorrhage, or facial nerve palsy)

230 small for gestational age17 and large for gestational age17. Exploratory maternal outcomes

231 were: cervical laceration, uterine rupture, hypertensive disorders of pregnancy (preeclampsia/

232 hypertension/eclampsia), venous thromboembolism, duration of stay in hospital, admission to

233 intensive care unit and mortality within 42 days.

234 Data collection

235 Data on maternal background, pregnancy and delivery characteristics, and neonatal outcomes

236 was retrieved from the Swedish Pregnancy Register16 and the Swedish Neonatal Quality

237 Register .18 Both registers are certified National Quality Registers initiated by Swedish

238 healthcare professionals. Data prospectively entered in standardised electronic medical

239 records by midwifes and clinicians during pregnancy, delivery and postpartum, is forwarded

240 to the Swedish Pregnancy Register from all antenatal clinics and most delivery clinics. In the

241 same way, the Swedish Neonatal Quality Register collects data on all newborns admitted to

242 NICU at birth or within 28 days of life. Vital statistics on maternal and neonatal mortality was

243 obtained from Statistics Sweden.

244 Study data was linked with data from the Swedish Pregnancy Register, the Swedish Neonatal

245 Quality Register and Statistics Sweden using the unique personal identification number

246 allocated to each person in Sweden at birth or immigration.19.

247

248 In all newborns with a primary outcome the medical records were collected and scrutinised,

249 and the same procedure was undertaken in all women with a diagnosis of endometritis to rule

250 out misclassification of sepsis.

251 To estimate selection bias, baseline characteristic and pregnancy outcome of our study

252 population was compared with the Swedish background population.

253

254 Monitoring

255 Before start, an independent Data and Safety Monitoring Board (DSMB) was formed,

256 comprising one statistician, one senior obstetrician and one senior midwife, with the role to

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257 supervise the trial through periodical reviews. Serious adverse events were immediately

258 reported by the principle investigators to DSMB and defined as any of: perinatal or maternal

259 death, neonate in need of neonatal intensive care because of meconium aspiration syndrome,

260 asphyxia, intracranial haemorrhage or other severe condition; severe maternal morbidity with

261 admission to intensive care unit; complication associated with induction of labour, e.g.

262 placental abruption at insertion of Foley catheter or uterine rupture.

263 An interim analysis was planned when 50% of the women were recruited and delivered.

264

265 Sample size and statistical analyses

266 To reduce the primary outcome by one third, from 2.74% to 1.84% (superiority testing, level

267 of significance 0.05, power 80%) by induction of labour at 41 weeks as compared with

268 expectant management until induction at 42 weeks a sample size of 10 038 women was

269 needed, 5019 in each randomisation group. This calculation was based on an assumption that

270 for 10% of the women, management would not be consistent with the assigned strategy, thus

271 also covering the same power for the per protocol analysis as for the intention to treat (ITT)

272 analysis. The composite primary outcome of 2.74% was based on data on perinatal outcomes

273 included in our primary outcome in one Swedish region (Region Skåne) between 2000 and

274 2010.

275 The statistical analyses were carried out according to a pre-specified analysis plan. Main

276 analyses were performed on the ITT population. The primary statistical analysis was the

277 comparison between the induction group and the expectant management group regarding the

278 primary perinatal composite outcome with two-sided Fisher’s exact test at significance level

279 0.05. To compare secondary outcomes, Fisher’s exact test was used for dichotomous

280 variables, Fisher’s non-parametric permutation test for continuous variables, Mantel Haenszel

281 chi-square test for ordered categorical variables and Pearsons’s chi-square test for non-

282 ordered categorical variables. Relative risk (RR) with 95% confidence interval (CI) between

283 the groups was calculated for the primary efficacy variable (the perinatal composite outcome)

284 and dichotomous secondary variables. Accordingly, mean differences with 95% CI between

285 the groups were calculated for continuous secondary variables. Data is presented by mean

286 with standard deviation (SD), median with 1st and 3rd interquartile range (IQR), number and

287 percentage, as appropriate.

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288 The ITT population included all randomised women except those withdrawing consent or lost

289 to follow up. Women with spontaneous labour or prelabour rupture of membranes after

290 randomisation but before induction were included in the ITT group, as were women with

291 pregnancy complications necessitating interventions for medical reasons.

292 A post-hoc sensitivity analysis for the primary efficacy analysis was performed adjusted for

293 the minimisation variables centre and primiparity/multiparity using multivariable logistic

294 regression analysis with centre as fixed effect.

295 Complementary analyses were performed for comparison of the primary perinatal composite

296 outcome and secondary efficacy outcomes on the per protocol population. The per protocol

297 population comprised all randomised women who completed the study without significant

298 protocol deviation. Protocol deviation criteria were defined before start of analysing the data

299 and included for the induction group: induction <41+0 weeks; labour induction, spontaneous

300 labour or caesarean delivery >41+2 weeks due to scheduling error or delivery room

301 unavailability; patient or provider preference; non-medically indicated elective caesarean

302 delivery. For the expectant management group protocol deviation was defined as: induction

303 >42+1 weeks; induction of labour <42 weeks due to scheduling error or patient or provider

304 preference; non-medically indicated elective caesarean delivery.

305 Prespecified subgroup variables were maternal age (≥35 years), nulliparity and BMI (BMI

306 ≥30). Logistic regression with treatment subgroup variable and the interaction term treatment

307 x subgroup variable was used to test whether the effect of treatment differed between

308 subgroups.

309 All significant tests were two-sided at the 0.05 significance level. All statistical analyses were

310 performed with SAS System Version 9 for Windows, SAS Inc., Cary, NC, USA.

311

312 Patient and public involvement

313 Pregnant women were not involved in the design, outcome measures, recruiting plans of the

314 study, and were not asked to give advice on interpretation of results. The results of the

315 research will be disseminated to the participants and general public through broadcasting,

316 popular science articles and newspapers.

317

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318 Results

319 On October 2, 2018 the DSMB strongly recommended the steering committee of SWEPIS to

320 stop the study owing to a statistically significant higher perinatal mortality in the expectant

321 management group. Perinatal mortality was a secondary outcome, yet, it was not considered

322 ethically correct to continue the study. There were no perinatal deaths in the early induction

323 group, but six perinatal deaths in the expectant management group (five stillbirths and one

324 early neonatal death) (p=0.031).

325 Recruitment took place from May 20, 2016 through October 13, 2018. Oral and written

326 informed consent was obtained from 2762 women who underwent randomisation, 1383

327 women were assigned to induction at 41 weeks and 1379 were assigned to expectancy until

328 induction at 42 weeks if needed (Figure 1). Recruitment according to trial centre is shown in

329 in the Appendix, Supplementary Table A. After randomisation but before intervention, two

330 women (induction group) withdrew their consent to participate and for their data to be used,

331 thus 1381 women in the induction group and 1379 women in the expectant management

332 group were included in the ITT analysis.

333 The two groups were similar at baseline (Table 1).

334

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335 Table 1 Baseline characteristics of intention to treat population

VariableInduction group

(n=1381)

Expectant management group

(n=1379)

Age at randomisation, years 31.2 (4.7)31.1 (28.0; 34.6)

n=1381

31.1 (4.5)30.9 (27.9; 34.2)

n=1379

Age at randomisation

Age at randomisation <35 years 1078/1381 (78.1%) 1100/1379 (79.8%)

Age at randomisation >=35 years 303/1381 (21.9%) 279/1379 (20.2%)

Parity (includes stillborn and live births)

Nulliparous 762/1381 (55.2%) 753/1379 (54.6%)

Parous 619/1381 (44.8%) 626/1379 (45.4%)

Smoking at first antenatal visit

No 1242/1274 (97.5%) 1228/1267 (96.9%)

1-9 cig/day 25/1274 (2.0%) 30/1267 (2.4%)

10 or more cig/day 7/1274 (0.5%) 9/1267 (0.7%)

Alcohol screening (AUDIT) at first antenatal visit*

0-5 points (low risk) 1102/1197 (92.1%) 1109/1190 (93.2%)

> = 6 (risk behavior) 95/1197 (7.9%) 81/1190 (6.8%)

Medical history

Psychiatric disease 95/1001 (9.5%) 108/997 (10.8%)

Prepregnancy diabetes mellitus type 1 or 2 2/1365 (0.1%) 0/1355 (0.0%)

Endocrine disease 83/1362 (6.1%) 97/1355 (7.2%)

Chronic hypertension 2/1362 (0.1%) 1/1353 (0.1%)

Height (cm) at first antenatal visit 167.5 (6.2)167 (163; 172)

n=1275

167.6 (5.9)168 (163; 172)

n=1273

Weight (kg) at first antenatal visit 70.0 (14.3)67 (60; 77)

n=1247

70.7 (14.5)68 (60; 77)

n=1241

BMI at first antenatal visit 24.9 (4.7)23.9 (21.6; 27.1)

n=1275

25.1 (4.9)24.0 (21.7; 27.4)

n=1265

BMI at first antenatal visit <30 1118/1275 (87.7%) 1081/1265 (85.5%)

BMI at first antenatal visit >=30 157/1275 (12.3%) 184/1265 (14.5%)

Last recorded weight during pregnancy, kg 83.5 (14.4)82.0 (74.0; 91.0)

n=1344

84.0 (14.6)82.0 (74.0; 92.0)

n=1336

Region of birth

Sweden 1069/1289 (82.9%) 1070/1298 (82.4%)

Other Nordic countries 74/1289 (5.7%) 84/1298 (6.5%)

Europe outside Nordic countries 20/1289 (1.6%) 18/1298 (1.4%)

Outside Europe 126/1289 (9.8%) 126/1298 (9.7%)

Highest education

Shorter than 9 years 7/1221 (0.6%) 10/1242 (0.8%)

At least 9 years primary school 47/1221 (3.8%) 47/1242 (3.8%)

High school 9 to 12 years 378/1221 (31.0%) 405/1242 (32.6%)

University or corresponding 789/1221 (64.6%) 780/1242 (62.8%)

Employment status

Employed 1098/1296 (84.7%) 1105/1301 (84.9%)

Student 101/1296 (7.8%) 101/1301 (7.8%)

Maternity leave 47/1296 (3.6%) 52/1301 (4.0%)

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VariableInduction group

(n=1381)

Expectant management group

(n=1379)

Unemployed 17/1296 (1.3%) 18/1301 (1.4%)

Sick leave 15/1296 (1.2%) 9/1301 (0.7%)

Other 18/1296 (1.4%) 16/1301 (1.2%)

Cohabitation with partner 1215/1360 (89.3%) 1211/1353 (89.5%)

Living alone/One person household 19/1360 (1.4%) 21/1352 (1.6%)

Mode of conception

Assisted conception (IVF/ICSI) 67/1381 (4.9%) 53/1379 (3.8%)

Subfertility 160/1250 (12.8%) 146/1199 (12.2%)

BMI=body mass index, IVF= in vitro fertilization, ICSI=intracytoplasmic sperm injectionFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median (interquartile range [IQR] Q1; Q3) / n= is presented.

*alcohol screening by AUDIT tool according to antenatal care routines20

336

337

338 Compared with the Swedish background population, women in the study groups had a higher

339 level of education and were more often born in Sweden (Appendix, Supplementary Table B).

340 In the induction group, 14.1% (195/1381) of the women had spontaneous onset of labour,

341 85.5% (1181/1381) underwent induction, of whom 76.6% (905/1181) had cervical ripening,

342 and 0.4% (5/1381) had a scheduled caesarean delivery (Table 2).

343

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344 Table 2 Delivery outcomes in intention to treat population

Variable Induction group(n=1381)

Expectant management

group(n=1379)

Relative Risk(95% CI) P value

Difference between groupsMean (95% CI)

Gestational age at delivery (days) 288.8 (1.3)289

(288; 289)n=1381

291.7 (2.7)292

(289; 294)n=1379

<0.001 -2.91 (-3.07 to -2.76)

Time from randomisation to delivery (days)

1.76 (1.42)2

(1; 2)n=1381

4.66 (2.64)4

(2; 7)n=1379

<0.001 -2.91 (-3.06 to -2.75)

Time from admittance to labour ward to delivery (hours)

20.1 (14.8)16.2

(9.2; 27.9)n=1380

13.6 (12.2)10.4

(4.6; 19.0)n=1378

<0.001 6.49 (5.50 to 7.50)

Onset of birth process Spontaneous 195/1381 (14.1%) 920/1379 (66.7%)

Scheduled caesarean delivery 5/1381 (0.4%) 2/1379 (0.1%)

Induction 1181/1381 (85.5%)

457/1379 (33.1%)

Mode of inductionCervical ripening 905/1181 (76.6%) 340/457 (74.4%)

Amniotomy without oxytocin 130/1181 (11.0%) 45/457 (9.8%)

Amniotomy with oxytocin 146/1181 (12.4%) 72/457 (15.8%) 0.18

Cervical ripeningFirst method mechanical 343/905 (37.9%) 126/340 (37.1%) 0.99 (0.90 to

1.09)

First method pharmacological 562/905 (62.1%) 214/340 (62.9%) 0.99 (0.90 to 1.09)

0.84

Indication for inductionRandomisation to 41 weeks and induction according to protocol

1146/1181 (97.0%)

0/457 (0.0%)

Randomisation to 42 weeks and induction according to protocol

0/1181 (0.0%) 373/457 (81.6%)

Maternal condition 1/1181 (0.1%) 41/457 (9.0%)

Fetal condition 0/1181 (0.0%) 18/457 (3.9%)

Maternal request* 7/1181 (0.6%) 23/457 (5.0%)

Other† 28/1181 (2.4%) 5/457 (1.1%)

Labour Duration of labour 7.13 (5.39)

5.67(2.85; 10.28)

n=717

8.32 (5.94)6.86

(3.76; 11.45)n=880

<0.001 -1.19 (-1.76 to -0.64)

Use of epidural anaesthesia 729/1381 (52.8%) 669/1379 (48.5%) 1.09 (1.01 to 1.17)

0.027

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group(n=1379)



Meconium stained amniotic fluid 233/1238 (18.8%) 320/1127 (28.4%) 0.66 (0.57 to 0.77)

<0.001

Mode of delivery Non-instrumental vaginal delivery 1150/1381

(83.3%)1140/1379 (82.7%) 1.01 (0.97 to

1.04)0.71

Caesarean delivery 143/1381 (10.4%) 148/1379 (10.7%) 0.96 (0.78 to 1.20)

0.79

Assisted vaginal delivery 88/1381 (6.4%) 91/1379 (6.6%) 0.97 (0.73 to 1.28)

0.87

Emergency caesarean delivery 138/143 (96.5%) 146/148 (98.6%) 0.98 (0.94 to 1.01)

0.42

Indication emergency caesarean delivery

Failed induction‡ 8/138 (5.8%) 7/146 (4.8%)

Failure to progress at first stage 60/138 (43.5%) 53/146 (36.3%)

Fetal distress at first stage 35/138 (25.4%) 28/146 (19.2%)

Failure to progress and fetal distress at first stage

6/138 (4.3%) 7/146 (4.8%)

Other indication at first stage 5/138 (3.6%) 5/146 (3.4%)

Failure to progress at second stage 11/138 (8.0%) 23/146 (15.8%)

Fetal distress at second stage 6/138 (4.3%) 8/146 (5.5%)

Failure to progress and fetal distress at second stage

0/138 (0.0%) 3/146 (2.1%)

Failure operative vaginal delivery 7/138 (5.1%) 12/146 (8.2%) 0.27

Indication assisted vaginal deliveryFailure to progress 37/88 (42.0%) 28/91 (30.8%)

Fetal distress 33/88 (37.5%) 34/91 (37.4%)

Failure to progress and fetal distress

5/88 (5.7%) 7/91 (7.7%)

Maternal distress 13/88 (14.8%) 21/91 (23.1%)

Other 0/88 (0.0%) 1/91 (1.1%) 0.35

Duration of hospital stay from delivery to discharge (hours)

46.3 (27.0)43.6

(25.3; 61.6)n=1333

47.1 (29.7)44.8

(25.8; 61.2)n=1333

0.46 -0.82 (-2.99 to 1.32)

Breast feeding at discharge from delivery hospital

987/1019 (96.9%) 981/1014 (96.7%) 1.00 (0.99 to 1.02)

0.98

Breastfeeding 4 weeks after delivery 835/923 (90.5%) 824/939 (87.8%) 1.03 (1.00 to 1.06)

0.071

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group(n=1379)



CI= confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presented.For comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables Fisher´s Exact test (2-sided) was used for dichotomous variables and Fisher´s Non-Parametric Permutation test was used for continuous variables.*maternal request outside study protocol e.g. women in the early induction group were induced on request after 41+1 weeks and women in the expectant management group were induced on request before 42+0 weeks†induction outside study protocol due to administrative errors or lack of capacity on labour ward‡ caesarean section performed when active labour was not reached despite different methods for induction of labour being used, usually for at least 48 hours

345 In the expectant management group, 66.7% (920/1379) of the women had spontaneous onset

346 of labour, 33.1% (457/1379) were induced, of whom 74.4% (340/457) had cervical ripening,

347 and 0.1% (2/1379) had a scheduled caesarean delivery. In 3.5% (48/1381) of women in the

348 induction group and in 2.0% (28/1379) of women in the expectant management group the

349 management was not consistent with the assigned strategy (Figure 1).

350 Median (IQR) time from randomisation to delivery was 2 (1; 2) days in the induction group

351 and 4 (2; 7) days in the expectant management group (p<0.001) (Table 2, Figure 2). Median

352 (IQR) gestational age at delivery was 289 (288; 289) days in the induction group and 292

353 (289; 294) days in the expectant management group (p<0.001).

354

355

356

357 Primary outcome

358 The primary outcome occurred in the induction group in 2.4% (33/1381) and in the expectant

359 management group in 2.2% (31/1379) (RR 1.06; 95% CI 0.65 to 1.73; p=0.90) (Table 3).

360

361

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362 Table 3 Perinatal outcome in intention to treat groups

VariableInduction

group(n=1381)


group(n=1379)



Primary composite outcome 33/1381 (2.4%) 31/1379 (2.2%) 1.06 (0.65 to 1.73)

0.90

Sub-components of the primary composite outcomePerinatal/neonatal mortality (stillbirth + neonatal mortality)

0/1381 (0.0%) 6/1379 (0.4%) 0.031

Stillbirth 0/1381 (0.0%) 5/1379 (0.4%) 0.062

Neonatal mortality (Live births with death day 0-27)

0/1381 (0.0%) 1/1378 (0.1%) 1.00

Neonatal morbidity 33/1381 (2.4%) 26/1374 (1.9%) 1.27 (0.76 to 2.11)

0.43

Sub-components of neonatal morbidityApgar score <7 at 5 minutes* 18/1381 (1.3%) 16/1374 (1.2%) 1.12 (0.57 to

2.19)0.88

Metabolic acidosis (denominator based on validated umbilical cord blood samples at birth)†

14/661 (2.1%) 10/644 (1.6%) 1.36 (0.61 to 3.05)

0.58

Hypoxic ischaemic encephalopathy (HIE) I-III

2/1381 (0.1%) 3/1374 (0.2%) 0.66 (0.11 to 3.96)

1.00

Intracranial haemorrhage 1/1381 (0.1%) 2/1374 (0.1%) 0.50 (0.05 to 5.48)

1.00

Neonatal convulsions 1/1381 (0.1%) 3/1374 (0.2%) 0.33 (0.03 to 3.18)

0.62

Meconium aspiration syndrome (MAS)

2/1381 (0.1%) 3/1374 (0.2%) 0.66 (0.11 to 3.96)

1.00

Mechanical ventilation within first 72 hours

3/1381 (0.2%) 5/1374 (0.4%) 0.60 (0.14 to 2.49)

0.72

Obstetric brachial plexus injury 4/1381 (0.3%) 1/1374 (0.1%) 3.98 (0.45 to 35.56)

0.38

Additional secondary neonatal outcome variablesAdmittance to neonatal intensive care units (NICU)

55/1381 (4.0%) 82/1374 (6.0%) 0.67 (0.48 to 0.93)

0.021

Apgar score <4 at 5 minutes* 3/1381 (0.2%) 1/1374 (0.1%) 2.98 (0.31 to 28.66)

0.63

Therapeutic hypothermia 1/1381 (0.1%) 2/1374 (0.1%) 0.50 (0.05 to 5.48)

1.00

Macrosomia (>= 4500 g) 68/1381 (4.9%) 114/1379 (8.3%)

0.60 (0.45 to 0.80)

0.001

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VariableInduction

group(n=1381)


group(n=1379)



Birthweight (g) 3815 (409)3804

(3536; 4090)n=1381

3875 (436)3865

(3570; 4160)n=1379

0.001 -60.1 (-91.8 to -29.6)

Neonatal jaundice requiring phototherapy or exchange transfusion

16/1381 (1.2%) 32/1374 (2.3%) 0.50 (0.27 to 0.90)

0.027

Pneumonia 8/1381 (0.6%) 13/1374 (0.9%) 0.61 (0.25 to 1.47)

0.38

Sepsis 9/1381 (0.7%) 20/1374 (1.5%) 0.45 (0.20 to 0.98)

0.058

Exploratory neonatal outcome variablesDays at neonatal intensive care units (NICU)

3.38 (2.97)2

(1; 6)n=55

4.59 (5.64)3 (0; 31)

(1; 6)n=81‡

0.15 -1.21 (-2.78 to 0.20)

Admittance to neonatal intensive care units (NICU) >4 days

34/55 (61.8%) 45/81 (55.6%) 1.11 (0.84 to 1.48)

0.58

Hypoglycaemia§ 22/1381 (1.6%) 20/1374 (1.5%) 1.09 (0.60 to 2.00)

0.89

Birth trauma¶ 0/1381 (0.0%) 1/1374 (0.1%) 1.00

Small for gestational age (SGA)** 9/1381 (0.7%) 22/1379 (1.6%) 0.41 (0.19 to 0.88)

0.028

Large for gestational age (LGA)** 21/1381 (1.5%) 26/1379 (1.9%) 0.81 (0.46 to 1.43)

0.55

Any major birth defect†† 14/1381 (1.0%) 17/1379 (1.2%) 0.82 (0.41 to 1.66)

0.72

Female 600/1381 (43.4%)

623/1379 (45.2%)

0.96 (0.88 to 1.05)

0.38

CI=confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presentedFor comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables Fisher´s Exact test (2-sided) was used for dichotomous variables and Fisher´s Non-Parametric Permutation test was used for continuous variables *Apgar score of live births†validated umbilical cord samples defined as values of arterial pH <venous pH and velues of arterial pCO2 >venous pCO2‡one infant with only home based neonatal care§hypoglycaemia defined as P-glucose concentration < 2,6 mmol/L after 3 hours¶defined as any of long bone fracture, clavicular fracture, skull fracture, other neurological injury, retinal haemorrhage, facial nerve palsy**SGA and LGA defined as <-2 SD and >2 SD, respectively, according to the Swedish sex specific reference17

††minor birth defects according to EUROCAT definition excluded21

363

364 There were no cases of stillbirth or neonatal mortality (0-27 days) in the induction group

365 (mortality rate 0.0%), whereas there were five stillbirths and one neonatal death (mortality

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366 rate 0.4%) in the expectant management group (p=0.031) occurring between 41+2 weeks and

367 41+6 weeks. One stillbirth occurred at the labour ward close after admittance. The

368 postmortem examination showed a cardiovascular malformation which according to

369 specialists in paediatric cardiology could not be considered as lethal. There were no

370 explanations to the stillbirths in the other four cases. One stillborn neonate was small for

371 gestational age, the other stillborns had birthweights within normal range. The neonatal death

372 occurred due to HIE in a neonate being large for gestational age.

373 A low Apgar score (<7 at 5 minutes) was the main contributor to the primary outcome: 1.3%

374 (18/1381) in the induction group compared with 1.2% (16/1374) in the expectant management

375 group (RR 1.12; 95% CI 0.57 to 2.19; p=0.88).

376 The post-hoc sensitivity analysis for the primary outcome with adjustment for the

377 minimisation variables centre and parity showed similar results (RR 1.05; 95% CI 0.65 to

378 1.59; p=0.85).

379 Secondary neonatal outcomes

380 Secondary neonatal outcomes are shown in Table 3. An Apgar score <4 at 5 minutes occurred

381 in 0.2% (3/1381) in the induction group and in 0.1% (1/1374) in the expectant management

382 group (RR 2.98; 95% CI 0.31 to 28.66; p=0.58). Fewer newborns in the early induction group

383 were admitted to NICU; 4.0% (55/1381) in the early group versus 6.0% (82/1374) in the

384 expectant management group (RR 0.67; 95% CI 0.48 to 0.93; p=0.021). If neonates with a

385 major birth defect (n=10) were excluded (antenatally detected major birth defect was an

386 exclusion criterion at study entry) there was no significant difference in admittance to NICU.

387 Fewer neonates in the induction group had hyperbilirubinemia treated with phototherapy or

388 exchange transfusion; 1.2% (16/1381) in the early group versus 2.3% (32 (1374) in the

389 expectant management group (RR 0.50; 95% CI 0.27 to 0.90; p=0.027). Macrosomia were

390 lower in the induction group than in the expectant management group (4.9% [68/1381] versus

391 8.3% [114/1379], RR 0.60; 95% CI 0.45 to 0.80; p<0.001). Other secondary outcomes did not

392 differ.

393 Maternal outcomes

394 Secondary maternal outcomes are presented in Table 2 and 4. Use of epidural anaesthesia was

395 higher in the induction compared with the expectant management group (52.8% [729/1381]

396 versus 48.5% [669/1379] (RR 1.09; 95% CI 1.01 to 1.17; p=0.027). Median (IQR) duration of

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397 labour was shorter 5.7 hours (2.9; 10.3) in the induction group compared with 6.9 hours (3.8;

398 11.5) in the expectant management group, respectively (p<0.001). Mode of delivery was

399 similar in both groups with rate of caesarean delivery of 10.4% (143/1381) in the induction

400 group and 10.7% (148/1379) in the expectant management group (RR 0.96; 95% CI 0.78 to

401 1.20); p=0.79). Indications for caesarean delivery did not differ between the groups.

402 Endometritis occurred in 1.3% (18/1381) and 0.4% (6/1379) in the induction and expectant

403 management groups (RR 3.0; 95% CI 1.19 to 7.52); p=0.022), respectively. Other secondary

404 adverse maternal outcomes including postpartum haemorrhage and perineal lacerations grade

405 III and IV were similar in both groups (Table 4).

406 Hypertensive disorders of pregnancy after randomisation (exploratory outcome) was lower in

407 the induction group compared with the expectant management group (1.4% [19/1381] versus

408 3.0% [42/1379], RR 0.45; 95% CI 0.26 to 0.77; p=0.004).

409

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410 Table 4 Maternal adverse outcomes in intention to treat population



group(n=1379)

Relative Risk(95% CI)

P value

Secondary maternal outcomesChorioamnionitis 2/1381 (0.1%) 6/1379 (0.4%) 0.33 (0.07 to 1.65) 0.29

Shoulder dystocia 6/1381 (0.4%) 4/1379 (0.3%) 1.50 (0.42 to 5.30) 0.76

Perineal lacerations III-IV 40/1381 (2.9%) 50/1379 (3.6%) 0.80 (0.53 to 1.20) 0.33

Postpartum haemorrhage (>1000 ml) 140/1381 (10.1%) 146/1379 (10.6%) 0.96 (0.77 to 1.19) 0.75

Wound infection 4/1381 (0.3%) 3/1379 (0.2%) 1.33 (0.30 to 5.94) 1.00

Urinary tract infection including pyelonephritis

5/1381 (0.4%) 7/1379 (0.5%) 0.71 (0.23 to 2.24) 0.77

Endometritis 18/1381 (1.3%) 6/1379 (0.4%) 3.00 (1.19 to 7.52) 0.022

Sepsis 0/1381 (0.0%) 0/1379 (0.0%) 1.00

Exploratory maternal outcomesPreeclampsia/gestational hypertension/eclampsia

19/1381 (1.4%) 42/1379 (3.0%) 0.45 (0.26 to 0.77) 0.004

Uterine rupture 0/1381 (0.0%) 0/1379 (0.0%) 1.00

Cervical laceration 5/1381 (0.4%) 8/1379 (0.6%) 0.62 (0.20 to 1.90) 0.58

Venous thromboembolism 0/1381 (0.0%) 1/1379 (0.1%) 1.00

Maternal admission to intensive care unit

2/1381 (0.1%) 0/1379 (0.0%) 0.50

Maternal death 0/1381 (0.0%) 0/1379 (0.0%) 1.00CI= confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presented.For comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables Fisher´s Exact test (2-sided) was used for dichotomous variables and Fisher´s Non-Parametric Permutation test was used for continuous variables.

411

412

413 Per protocol analysis

414 The prespecified analysis of the per protocol population included 1333 women in the

415 induction group and 1351 women in the expectant management group. Reasons for protocol

416 violation are shown in Figure 1. Baseline characteristics were similar between the groups

417 (Appendix, Supplementary Table C). The primary perinatal adverse outcome occurred in 31

418 cases in the induction group and in 31 cases in the expectant management group (RR 1.01;

419 95% CI 0.62 to 1.66; p=1.0) (Appendix, Supplementary Table E). There were no cases of

420 stillbirth or neonatal mortality (0-27 days) in the induction group (mortality rate 0.0%),

421 whereas there were five stillbirths and one neonatal death (mortality rate 0.4%) in the

422 expectant management group (p=0.032).

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423 Secondary neonatal and maternal outcomes are shown in Appendix, Supplementary Table D

424 to F.

425 Subgroup analyses

426 Prespecified subgroup analyses on the primary outcome and selected secondary outcomes

427 according to parity (parity 1 versus parity>1), maternal age (<35 years versus ≥35 years) and

428 BMI (BMI <30 versus BMI ≥30) were performed on the ITT population. In the ITT

429 population, analyses of primary outcome showed no significant difference in the treatment

430 effect according to parity, age or BMI (p=0.29, p=0.70, p=0.51, respectively, for the

431 interaction). In total, there were five stillbirths and one early neonatal death, and all of them

432 occurred in the expectant management group; in nulliparous 0.8% (6/753) versus in parous

433 women 0% (0/626), in women ≥35 years 1.1% (3/279) versus in women <35 years 0.3%

434 (3/1100) and in women with BMI ≥30 1.1% (2/184) versus in women with BMI <30 0.4%

435 (4/1081). Due to the low mortality rate (n=6) no interaction analysis on mortality could be

436 performed. Among nulliparous women, rate of caesarean delivery was 16.7% (127/762) in the

437 induction and 17.3% (130/753) in the expectant management group (p=0.81).

438 When testing if the effect of induction versus expectant management was similar across

439 centres (Stockholm centres versus other centres i.e. offering a routine ultrasound scan at 41+0

440 weeks or not) no significant interaction effect was found for the primary outcome (p=0.19) in

441 the ITT population. Perinatal mortality in the expectant management group was 0.0% (0/557)

442 in Stockholm versus 0.7% (6/822) in the other centres.

443

444

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445 Discussion

446 In this large randomised trial, comparing induction of labour at 41 weeks versus expectant

447 management until induction at 42 weeks, we found no significant difference in the primary

448 composite adverse perinatal outcome, 33/1381 (2.4%) and 31/1379 (2.2%) in the induction

449 and expectant management groups, respectively (RR 1.06; 95% CI 0.65 to 1.73, p=0.90). Yet,

450 the perinatal mortality was significantly lower in the induction group (no deaths) compared

451 with the expectant management group (five intrauterine deaths, one neonatal death)

452 (p=0.031). Furthermore, there was lower admittance to NICU, fewer infants with neonatal

453 jaundice requiring therapy and fewer macrosomic infants in the induction group. This study

454 found no significant difference in caesarean delivery rates between groups.

455 Comparison with previous studies

456 Postterm (≥42 weeks) pregnancy is associated with an increased risk of adverse perinatal

457 morbidity and mortality.3-5 In fact, the risk appears to increase gradually after 39 weeks.3,4,13

458 Results from most meta-analyses indicate that a policy of induction before 42 full weeks is

459 associated with decreased perinatal mortality.9, 22-24

460 All perinatal deaths occurred in nulliparous women. Nulliparity is not always recognised as a

461 factor conferring increased risk of perinatal mortality,2,25,26 but our results agree with a

462 Swedish register study where stillbirths were significantly more common in nulliparous than

463 in multiparous women and the rise in neonatal mortality was seen at 41+ weeks in nulliparous

464 but not until 42 weeks of gestation in multiparous womens3. If this finding can be replicated

465 in future studies, it could mean that nulliparous women may require particular attention and

466 interventions such as labour induction could be particularly important in this group.

467 The benefit of early induction is supported by a recently published open label multicentre

468 randomised trial (INDEX trial) from the Netherlands including 1801 women, in which

469 induction at 41 weeks was associated with a lower composite adverse perinatal outcome

470 (1.7%) compared with expectant management until 42 weeks (3.1%) (p=0.045).12 However,

471 the perinatal mortality rate did not differ significantly between the groups with one death in

472 the 41 weeks group and two in the 42 weeks group.

473 It could be argued that the higher mortality in the expectant management group in our study is

474 partly due to that fetal surveillance with CTG/ultrasound between 41 weeks and 42 weeks was

475 not pursued routinely unless clinical signs of complications occurred. Yet, the adverse

476 perinatal outcomes in general were not higher in the expectant management group in the

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477 SWEPIS compared with the INDEX trial and the median gestational age at delivery was

478 higher in the expectant management group in our trial (292 days) than in the INDEX trial

479 (289 days) which could augment mortality rates. No perinatal deaths occurred among women

480 recruited in the Stockholm region, where all women are offered a routine ultrasound at week

481 41+0 (before randomisation), aiming to identify women with an elevated risk for adverse

482 outcome. However, the rarity of perinatal death limits the power of a subanalysis by centre.

483 Further, two of the five HIE cases occurred in Stockholm and the composite neonatal

484 morbidity was similar in Stockholm (24/1122=2.1%) and in the other centres (34/1632=2.1%)

485 which does not support that the 41-week ultrasound was critical. It is also uncertain to what

486 extent ultrasound or CTG recordings usually performed at two or three day intervals can

487 prevent intrauterine or neonatal deaths7,26,27 and the evidence supporting that fetal monitoring

488 prevents complications of post-maturity is considered weak.7

489 The occurrence of endometritis was significantly higher in the 41 weeks’ group than in the

490 expectant management group which was unexpected but might well be a chance finding.

491 Recent studies indicate that the infectious morbidity is not higher for mechanical than

492 pharmacological methods for cervical dilation28 and the occurrence of endometritis is similar

493 or lower in our trial than reported in most studies on labour induction.28–30 Furthermore, the

494 frequency of other maternal (chorioamnionitis, wound infections, urinary tract infections) and

495 neonatal (sepsis, pneumonia) infections was not higher in the induction group.

496 Strengths and weaknesses of the trial

497 Strengths of the present study is that it concerns a large national multicentre randomised

498 controlled trial comparing induction at 41 weeks with expectant management until induction

499 at 42 weeks, the latter being standard of care in Sweden at present. Despite the fact that only a

500 minority of eligible women were informed or accepted participation (Figure 1), the study

501 population was representative of a Swedish low risk population according to most baseline

502 characteristics (Appendix, Supplementary Table B). Another strength is that the study

503 participants were managed at the same level of care and methods of induction were applied

504 irrespective of allocation arm, which was not always the case in previous randomised trials on

505 postterm pregnancies.12, 31

506 There were some limitations of the present trial. It could appear contradictory that a

507 significant difference was found between groups in perinatal mortality but yet no difference in

508 the composite adverse neonatal outcome. However, 5/6 deaths were stillbirths in the SWEPIS

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509 trial, which have a quite different aetiology and array of risk factors32 as compared with

510 neonatal mortality/morbidity.33 Placental abnormality/dysfunction, umbilical cord

511 complications, and growth restriction are considered causes of stillbirth2,32 that could well be

512 of increasing importance in late term/postterm pregnancy.

513 Another problem is that the composite primary outcome was defined maybe somewhat

514 broadly predominated by Apgar <7 at 5 minutes which according to recent data may be a

515 relatively weak predictor of more serious outcomes such as neurological morbidity and

516 mortality and Apgar <4 at 5 minutes is probably preferable34. On the other hand, the

517 advantage of composite outcomes is that the number of cases in each arm can be reduced and

518 execution of the study becomes more realistic.

519 Pregnant women were not involved in the design of the SWEPIS trial which is a limitation35

520 even though our firm impression is that management of late term and post term pregnancies is

521 a prioritised field of research for many women. However, we are addressing pregnant

522 women’s experiences in the 41 and 42 week groups in a separate survey which will be

523 published eventually.

524 The fact that half of the women (those recruited in the Stockholm region) underwent

525 ultrasound measurement of amniotic fluid volume and abdominal diameter at 41 weeks

526 whereas such examinations were not performed systematically at the other centres might be

527 regarded both as a limitation and a strength. It is difficult to determine whether outcomes

528 were affected by this difference in policy (see above) while such a management increases

529 generalisability and reflects current obstetric practice in Sweden.36

530 It is not clear whether the results are broadly generalisable. However, the study included

531 university, regional and local hospitals and women from 17 countries were eligible for

532 inclusion. Different methods for labour induction, according to local routines, were allowed

533 and one large region used an extra ultrasound scan in gestational week 41 before inclusion.

534 All these strategies contribute to increase in generalisability of the results.

535 Although many significance tests were performed, also for secondary and exploratory

536 outcomes, we have not corrected for multiple comparisons due to the risk of not finding

537 differences of high clinical importance for the patients. We instead leave it to the reader to

538 judge the relevance of these findings.

539

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540 Implications for clinicians and policy makers

541 In conclusion, the SWEPIS trial shows that induction of labour at 41 weeks versus expectant

542 management until 42 weeks does not alter the composite perinatal outcome, the primary

543 outcome of this study. However, a reduction of the secondary outcome perinatal mortality is

544 observed without increasing adverse maternal outcome. The number needed to treat with

545 induction of labour at 41 weeks to prevent one perinatal death was 250 which is lower than

546 previous estimates.9, 22, 23. Although these results should be interpreted cautiously, we suggest,

547 based on previous reports and the results of the present trial, that labour induction should be

548 offered women at 41+0 weeks12 or earlier11, 37 and could be one (of few) interventions that

549 reduces stillbirth.

550

551

552 Contributors: UBW and SS are joint first authors and contributed equally to the study.

553 UBW, HH, VS and HE conceived and designed the study. UBW, HH, AW, SS, AKW, MJ,

554 HF and JW oversaw recruitment of study participants and collection of data at the local

555 centres. UBW, HH, CB, HE, OS and SS wrote the Statistical Analysis Plan together with two

556 statisticians (Mattias Molin, Nils-Gunnar Pehrson, the Statistical Consulting Group,

557 Gothenburg). UBW and MA did the data cleaning together with statistician Mattias Molin and

558 Per Ekman. UBW, HH, CB, SS, MA, LL, VS, SBW, OS, GW, HE and AW interpreted the

559 data. UBW, MA, AW, SS and HH wrote the first draft of the manuscript, which was then

560 critically reviewed and revised by the other co-authors. All authors approved the final version

561 of the manuscript for submission.

562

563 The SWEPIS study group: The midwives and doctors responsible at the local centres:

564 Uppsala University Hospital: Irina Sylwe; South Älvsborg Hospital: Lena Loubelo, Carolina

565 Bergerum, Serney Bööj; Department of Gynecology Närhälsan, Mölndal: Maria Bullarbo;

566 Sahlgrenska University Hospital, Göteborg: PhD candidates Anna Wessberg and Helena

567 Nilver, Pia Hempel, Martina Söderlund, Erica Ginström Ernstad, Monica Eriksson Orrskog;

568 Stockholm: Karolinska University Hospital Huddinge and Solna, South Hospital, Danderyd

569 Hospital, South BB, Södertälje Hospital: Helen Fagraeus, Annelie Sjölund, Eva Itzel Wiberg;

570 Halland Hospital: Elisabeth Johansson, Sandra Holmström, Åsa Ponten, Maud Ankardal;

571 Örebro Hospital: Inger Nydahl, Sofia Saarväli, Camilla Hartin; Falun Hospital: Elisabeth

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572 Nordström, Kerstin Fransson, Visby Hospital: Madelen Jacobsson; North Älvsborg Hospital:

573 Maria Olsson, Anna Hagman.

574

575 Acknowledgements: Jonas Eriksson Söderling provided data from the Swedish Pregnancy

576 Register and performed the statistical analysis for the DSMB reports, Stellan Håkansson

577 provided data from the Swedish Neonatal Quality Register, Jesper Brodin provided data from

578 Statistics Sweden, Agneta Cedefors-Blom helped with secretarial assistance.

579 Mattias Molin and Per Ekman, the Statistical Consulting Group, Gothenburg, performed the

580 statistical analyses. Therese Svanberg at the Medical Library at Sahlgrenska University

581 Hospital performed the literature search.

582 We want to acknowledge the assistance given by the DSMB with Hans Wedel as chairman,

583 We also would like to thank all participating women.

584 Funding: The Swedish state under the agreement between the Swedish government and the

585 county councils, the ALF-agreement (ALFGBG-440301, ALFGBG-718721, ALFGBG-

586 70940, ALFGBG-426401), the Health Technology Centre (HTA) at Sahlgrenska University

587 Hospital, the Foundation of the Health and Medical care committee of the Region of Vastra

588 Gotaland, Sweden (VGFOUREG387351, VGFOUREG640891, VGFOUREG854081),

589 Hjalmar Svensson Foundation, the foundation Mary von Sydow, born Wijk, donation fund,

590 Uppsala-Örebro Regional Research Council (RFR-556711, RFR-736891), Region Örebro

591 County research Committee (OLL-715501), Region Stockholm ALF 561222, 562222,

592 563222, Center for Clinical Research Dalarna - Uppsala University, Sweden CKFUU –

593 417011.

594 The funders had no role in study design, data collection, data analysis, data interpretation, or

595 writing of the report.

596 Competing interest: All authors have completed the ICMJE uniform disclosure form

597 (available on request from the corresponding author) and declare: UBW, SS, AW, MA, CB,

598 SBW, HF, MJ, LL, VS, JW, GW, HE, OS, HH declare no competing interests. AKW has

599 received free reagents (PlGF) from Roche for a prediction study of preeclampsia.

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600 Ethical approval: The Regional Ethics Board in Gothenburg approved the study in May

601 2014 (Dnr: 285-14) and later its complementary applications (T 905-15, T 291-16, T 1180-16,

602 T 330-17, T 1066-17, T 087-18, T 347-18, T 961-18, T 1110-18).

603 Data sharing: The full data set is available from the corresponding author on reasonable

604 request.

605 Transparency: All authors had full access to all the data in the study and take responsibility

606 for the integrity of the data and the accuracy of the data analysis. The corresponding author

607 (UBW) affirms that this manuscript is an honest, accurate, and transparent account of the

608 study being reported; that no important aspects of the study have been omitted; and that any

609 discrepancies from the study as planned have been explained. The corresponding author

610 (UBW) had the final responsibility for the decision to submit for publication.

611

612

613

614

615

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717 36. Grunewald C, Hakansson S, Saltvedt S, Kallen K. Significant effects on

718 neonatal morbidity and mortality after regional change in management of post-term

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720 37 Walker KF, Bugg GJ, Macpherson M, McCormick C et al. Randomized Trial of

721 Labor Induction in Women 35 Years of Age or Older. N Engl J Med. 2016; 374 (9):813-22

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CONSORT 2010 Flow Diagram

Possible to assess for eligibility (n=19 079)

Excluded (n=6525) • Did not meet eligibility criteria (n=6018)

(Most of them had a planned induction of labour for maternal or fetal indication)

• Had spontaneous onset of labour at ≥41+0 weeks before randomisation (n=507)

Analysed according to intention to treat (n=1381) ♦ Excluded from analysis (n=0)

Lost to follow-up (n= 0)

Allocated to intervention and induction at 41 weeks (n=1383)

♦ Received allocated intervention (n=1333) ♦ Did not receive allocated intervention (n=48)

o Maternal request (n=13) o Administrative errors (n=19) o Lack of capacity on labour ward

(n=16) ♦ Withdrew consent before intervention (n=2)

Lost to follow-up (n=0)

Allocated to expectant management and induction at 42 weeks (n=1379)

♦ Received allocated intervention (n=1351) ♦ Did not receive allocated intervention (n=28)

o Maternal request (n=22) o Administrative errors (n=6)

Analysed according to intention to treat (n=1379) ♦ Excluded from analysis (n=0)

Allocation

Analysis

Follow-Up

Randomised (n=2762)

Enrollment

Eligible (n=12 554)

Declined (n=9792)

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Figure 2 Gestational age at delivery in intention to treat groups In the induction group n=1380 because one woman was incorrectly randomised before 40+6 weeks and

delivered before 40+6 weeks

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Supplementary Table A. Study period, number of possible eligible women, number of eligible women and number of included women at the participating centres

Study period* Number of possible eligible

women** during study

period

Number of eligible women during study period

Number of included women

Included women/number

of possible eligible women

Included women/number

of eligible women

Sahlgrenska University Hospital

May 20, 2016 to October 15 2018

4657 3020 776 16.7% 25.7%

UppsalaUniversity Hospital

February 2, 2017 to October 15, 2018

1531 1025 351 22.9% 34.2%

Falun Hospital

January 23, 2017 to October 15, 2018

874 565 119 13.6% 21.1%

South Älvsborg Hospital

April 6, 2017 to October 15, 2018

1038 665 158 15.2% 23.8%

Stockholm(Södertälje, Karolinska Solna, Karolinska Huddinge, Danderyd, South BB, South Hospital)

March 28, 2017 to October 15, 2018

8934 5960 1122 12.6% 18.8%

Örebro University Hospital

September 9, 2017 to October 15, 2018

650 416 65 10.0% 15.6%

Halland Hospital, Varberg


585 372 78 13.3% 21.0%

Halland Hospital, Halmstad


470 305 53 11.3% 17.4%

Visby Hospital

March 2, 2018 to October 15, 2018

61 39 30 49.2% 76.9%

North Älvsborg Hospital

June 13, 2018 to October 15, 2018

279 187 10 3.6% 5.3%

Total May 20, 2016 to October 15, 2018

19 079 12 554 2760 14.5% 22.0%

*Most centres stopped recruitment for a period during June, July and August**Deliveries ≥41+0 gestational weeks, only one delivery per woman, first delivery during the study period, singleton, women ≥18 years, cephalic presentation. Women with previous caesarean delivery were excluded.

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Supplementary Table B Baseline characteristics of Swedish background population*

Variable

Swedish background population(n=49 779)

Age at delivery (years) Mean (SD) 30.8 (4.9)

Median (IQR) 30.6 (27.3; 34.1)

Age at delivery >=35 years 10 149 (20.4%)

Parity (includes stillborn and live births)Nulliparous 25 607 (51.4%)

Smoking at first antenatal visitNo 42 689 (85.8%)

Missing 5496 (11.0%)

BMI at first antenatal visit Mean (SD) 25.1 (4.8)

Median (IQR) 24.1 (21.8; 27.4)

BMI>=30 at first antenatal visit 6562 (13.2%)

BMI missing 4300 (8.6%)

Region of birthSweden 33 384 (67.1%)

Other Nordic countries 424 (0.9%)

Europe outside Nordic countries 3542 (7.1%)

Outside Europe 8338 (16.8%)

Missing 4091 (8.2%)

Highest level of educationNone or shorter than 9 years 1276 (2.6%)

At least 9 years primary school 2352 (4.7%)

High school 9 to 12 years 15 512 (31.2%)

University or corresponding 23 256 (46.7%)

Missing 7383 (14.8%)

Mode of conception Assisted conception (IVF/ICSI) 1825 (3.7%)

Gestational age (days) Mean (SD) 291 (3)

Median (IQR) 290 (288; 293)

Gestational age >/=42+0 weeks 12 129 (24.4%)

Birth weight, g Mean (SD) 3815 (452)

Median (IQR) 3800 (3500; 4110)

Missing 194 (0.4%)

SGA 899 (1.8%)

LGA 971 (2.0%)

Stillbirth 60 (0.12%)

Perinatal mortality (stillbirth and early neonatal death [<7 days]) 70 (0.14%)

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Apgar score < 4 at 5 min 172 (0.3%)

Apgar score < 7 at 5 min 706 (1.4%)

Missing Apgar score 156 (0.3%)

Cesarean section 4162 (8.4%)

BMI= body mass index, SGA=small for gestational age (<-2 SD according to the sex specific Swedish reference12; LGA=large for gestational age (> 2 SD according to the sex specific Swedish reference12, IVF= in vitro fertilization, ICSI= intracytoplasmic sperm injectionFor categorical variables n/N (%) is presentedFor continuous variables Mean (standard deviation [SD])/ Median, (interquartile range [IQR] Q1; Q3) is presented*From the Swedish Pregnancy Register: Deliveries ≥ 41+0 gestational weeks in Sweden during the study period between May 15, 2016 and October 15, 2018 (only one delivery per woman, first delivery during the study period), singleton, women ≥18 years, cephalic presentation. Women with previous caesarean delivery were excluded.

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Supplementary Table C Baseline characteristics of per protocol population



group(n=1351)

Age at randomisation, years 31.3 (4.7)31.1 (28.; 34.6)

n=1333

31.0 (4.5)30.9 (27.9; 34.2)

n=1351

Age at randomisationAge at randomisation <35 years 1039/1333 (77.9%) 1079/1351 (79.9%)

Age at randomisation >=35 years 294/1333 (22.1%) 272/1351 (20.1%)

Parity (includes stillborn and live births)Nulliparous 729/1333 (54.7%) 742/1351 (54.9%)

Parous 604/1333 (45.3%) 609/1351 (45.1%)

Smoking at first antenatal visitNo 1199/1231 (97.4%) 1201/1239 (96.9%)

1-9 cig/day 25/1231 (2.0%) 29/1239 (2.3%)

10 or more cig/day 7/1231 (0.6%) 9/1239 (0.7%)

Alcohol screening (AUDIT) at first antenatal visit*

0-5 points (low risk) 1068/1157 (92.3%) 1084/1164 (93.1%)

> = 6 (risk behavior) 89/1157 (7.7%) 80/1164 (6.9%)

Medical history Psychiatric disease 89/957 (9.3%) 106/974 (10.9%)

Prepregnancy diabetes mellitus type 1 or 2 1/1317 (0.1%) 0/1327 (0.0%)

Endocrine disease 77/1314 (5.9%) 94/1327 (7.1%)

Chronic hypertension 1/1314 (0.1%) 1/1325 (0.1%)

Height (cm) at first antenatal visit 167.4 (6.2)167 (163; 172)

n=1236

167.6 (5.9)168 (163; 172)

n=1246

Weight (kg) at first antenatal visit 69.9 (14.3)67 (60.; 76)

n=1211

70.7 (14.4)68 (60.; 77)

n=1216

BMI at first antenatal visit 24.9 (4.7)23.8 (21.6; 27.1)

n=1234

25.1 (4.9)24 (21.7; 27.3)

n=1239

BMI at first antenatal visit <30 1084/1234 (87.8%) 1059/1239 (85.5%)

BMI at first antenatal visit >=30 150/1234 (12.2%) 180/1239 (14.5%)

Last recorded weight during pregnancy, kg 83.5 (14.4)82 (74.; 91)

n=1298

84.0 (14.6)82 (74.; 92)

n=1308

Region of birthSweden 1035/1246 (83.1%) 1047/1272 (82.3%)

Other Nordic countries 71/1246 (5.7%) 82/1272 (6.4%)

Europe outside Nordic countries 20/1246 (1.6%) 18/1272 (1.4%)

Outside Europe 120/1246 (9.6%) 125/1272 (9.8%)

Highest educationShorter than 9 years 7/1177 (0.6%) 10/1217 (0.8%)

At least 9 years primary school 46/1177 (3.9%) 45/1217 (3.7%)

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group(n=1351)

High school 9 to 12 years 365/1177 (31.0%) 395/1217 (32.5%)

University or corresponding 759/1177 (64.5%) 767/1217 (63.0%)

Employment statusEmployed 1063/1251 (85.0%) 1082/1276 (84.8%)

Student 97/1251 (7.8%) 99/1276 (7.8%)

Maternity leave 45/1251 (3.6%) 52/1276 (4.1%)

Unemployed 16/1251 (1.3%) 18/1276 (1.4%)

Sick leave 15/1251 (1.2%) 9/1276 (0.7%)

Other 15/1251 (1.2%) 16/1276 (1.3%)

Cohabitation with partner 1174/1312 (89.5%) 1184/1325 (89.4%)

Living alone/One person household 19/1312 (1.4%) 21/1324 (1.6%)

Mode of conception Assisted conception (IVF/ICSI) 62/1333 (4.7%) 53/1351 (3.9%)

Subfertility 151/1207 (12.5%) 143/1173 (12.2%)BMI=body mass index, IVF= in vitro fertilization, ICSI=intracytoplasmic sperm injectionFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median (interquartile range [IQR] Q1; Q3) / n= is presented.

*alcohol screening by AUDIT tool according to antenatal care routines20

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Supplementary Table D Delivery outcomes in per protocol population



group(n=1351)


Difference between groups

Mean (95% CI)

Gestational age at delivery (days) 288.7 (1.1)289

(288; 289)n=1333

291.7 (2.7)292

(289; 294)n=1351

<0.001 -3.03 (-3.19 to -2.88)

Time from randomisation to delivery (days)

1.63 (1.03)2

(1; 2)n=1333

4.67 (2.65)4

(2; 7)n=1351

<0.001 -3.04 (-3.19 to -2.89)

Time from admittance to labour ward to delivery (hours)

20.1 (14.9)16.1

(9.2; 27.8)n=1332

13.6 (12.2)10.4

(4.6; 18.9)n=1350

<0.001 6.57 (5.53 to 7.59)

Onset of birth process Spontaneous 182/1333 (13.7%) 917/1351 (67.9%)

Scheduled caesarean delivery 5/1333 (0.4%) 2/1351 (0.1%)

Induction 1146/1333 (86.0%) 432/1351 (32.0%)

Mode of inductionCervical ripening 878/1146 (76.6%) 325/432 (75.2%)

Amniotomy without oxytocin 129/1146 (11.3%) 42/432 (9.7%)

Amniotomy with oxytocin 139/1146 (12.1%) 65/432 (15.0%) 0.24

Cervical ripeningFirst method mechanical 334/878 (38.0%) 118/325 (36.3%) 0.97 (0.88 to

1.07)

First method pharmacological 544/878 (62.0%) 207/325 (63.7%) 0.97 (0.88 to 1.07)

0.63

Indication for inductionRandomisation to 41 weeks and induction according to protocol

1145/1146 (99.9%) 0/432 (0.0%)

Randomisation to 42 weeks and induction according to protocol

0/1146 (0.0%) 373/432 (86.3%)

Maternal condition 1/1146 (0.1%) 41/432 (9.5%)

Fetal condition 0/1146 (0.0%) 18/432 (4.2%)

LabourDuration of labour 7.07 (5.42)

5.64 (2.83; 10.24)

n=692

8.37 (5.96)6.9

(3.78; 11.53)n=867

<0.001 -1.30 (-1.87 to -0.74)

Use of epidural anaesthesia 704/1333 (52.8%) 658/1351 (48.7%) 1.08 (1.01 to 1.17)

0.037

Meconium stained amniotic fluid 225/1192 (18.9%) 317/1101 (28.8%) 0.66 (0.56 to 0.76)

<0.001

Mode of delivery Non-instrumental vaginal delivery 1112/1333 (83.4%) 1118/1351 (82.8%) 1.01 (0.97 to

1.04)0.68

Caesarean delivery 134/1333 (10.1%) 144/1351 (10.7%) 0.94 (0.75 to 1.18)

0.65

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group(n=1351)


Difference between groups

Mean (95% CI)

Assisted vaginal delivery 87/1333 (6.5%) 89/1351 (6.6%) 0.99 (0.74 to 1.32)

1.00

Emergency caesarean delivery 129/134 (96.3%) 142/144 (98.6%) 0.98 (0.94 to 1.01)

0.39

Indication emergency caesarean delivery

Failed induction* 8/129 (6.2%) 7/142 (4.9%)

Failure to progress at first stage 55/129 (42.6%) 52/142 (36.6%)

Fetal distress at first stage 32/129 (24.8%) 27/142 (19.0%)

Failure to progress and fetal distress at first stage

6/129 (4.7%) 7/142 (4.9%)

Other indication at first stage 5/129 (3.9%) 3/142 (2.1%)

Failure to progress at second stage 11/129 (8.5%) 23/142 (16.2%)

Fetal distress at second stage 6/129 (4.7%) 8/142 (5.6%)

Failure to progress and fetal distress at second stage

0/129 (0.0%) 3/142 (2.1%)

Failure operative vaginal delivery 6/129 (4.7%) 12/142 (8.5%) 0.26

Indication assisted vaginal deliveryFailure to progress 36/87 (41.4%) 28/89 (31.5%)

Fetal distress 33/87 (37.9%) 34/89 (38.2%)

Failure to progress and fetal distress

5/87 (5.7%) 6/89 (6.7%)

Maternal distress 13/87 (14.9%) 20/89 (22.5%)

Other 0/87 (0.0%) 1/89 (1.1%) 0.47

Duration of hospital stay from delivery to discharge (hours)

46.3 (27.1)43.6

(25.3; 61.6)n=1286

47.3 (29.7)45

(26.5; 61.2)n=1305

0.36 -1.03 (-3.20 to 1.17)

Breast feeding at discharge from delivery hospital

949/979 (96.9%) 961/992 (96.9%) 1.00 (0.98 to 1.02)

1.00

Breast feeding 4 weeks after delivery 806/893 (90.3%) 814/927 (87.8%) 1.03 (1.00 to 1.06)

0.11

CI= confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presented.For comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables and Fisher´sNon-Parametric Permutation test was used for continuous variables*Caesarean section performed when active labour was not reached despite different methods for induction of labour being used, usually for at least 48 hours.

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Supplementary Table E Perinatal outcome in per protocol groups

VariableInduction

group(n=1333)


group(n=1351)



Primary composite outcome 31/1333 (2.3%) 31/1351 (2.3%) 1.01 (0.62 to 1.66)

1.00

Sub-components of the primary composite perinatal outcome Perinatal/neonatal mortality (stillbirth + neonatal mortality)

0/1333 (0.0%) 6/1351 (0.4%) 0.032

Stillbirth 0/1333 (0.0%) 5/1351 (0.4%) 0.064

Neonatal mortality (Live births with death day 0-27)

0/1333 (0.0%) 1/1346 (0.1%) 1.00

Neonatal morbidity 31/1333 (2.3%) 26/1346 (1.9%) 1.21 (0.72 to 2.02)

0.56

Sub-components of neonatal morbidityApgar score <7 at 5 minutes* 17/1333 (1.3%) 16/1346 (1.2%) 1.07 (0.54 to

2.11)0.98

Metabolic acidosis (denominator based on validated umbilical cord blood samples at birth)†

13/645 (2.0%) 10/633 (1.6%) 1.28 (0.56 to 2.89)

0.71

Hypoxic ischaemic encephalopathy (HIE) I-III

2/1333 (0.2%) 3/1346 (0.2%) 0.67 (0.11 to 4.02)

1.00

Intracranial haemorrhage 1/1333 (0.1%) 2/1346 (0.1%) 0.50 (0.05 to 5.56)

1.00

Neonatal convulsions 1/1333 (0.1%) 3/1346 (0.2%) 0.34 (0.04 to 3.23)

0.63

Meconium aspiration syndrome (MAS)

2/1333 (0.2%) 3/1346 (0.2%) 0.67 (0.11 to 4.02)

1.00

Mechanical ventilation within first 72 hours

3/1333 (0.2%) 5/1346 (0.4%) 0.61 (0.15 to 2.53)

0.74

Obstetric brachial plexus injury 4/1333 (0.3%) 1/1346 (0.1%) 4.04 (0.45 to 36.09)

0.37

Additional secondary neonatal outcomes variablesAdmittance to neonatal intensive care units (NICU)

55/1333 (4.1%) 82/1346 (6.1%) 0.68 (0.49 to 0.94)

0.026

Apgar score <4 at 5 minutes* 3/1333 (0.2%) 1/1346 (0.1%) 3.04 (0.32 to 29.19)

0.61

Therapeutic hypothermia 1/1333 (0.1%) 2/1346 (0.1%) 0.51 (0.05 to 5.58)

1.00

Birthweight (g) 3814 (409)3804

(3530; 4090)n=1333

3874 (435)3860

(3570; 4155)n=1351

0.001 -60.1 (-92.0 to-28.5)

Macrosomia (>= 4500 g) 64/1333 (4.8%) 112/1351 (8.3%)

0.58 (0.43 to 0.78)

0.001

Neonatal jaundice requiring phototherapy or exchange transfusion

16/1333 (1.2%) 32/1346 (2.4%) 0.51 (0.28 to 0.92)

0.031

Pneumonia 8/1333 (0.6%) 13/1346 (1.0%) 0.62 (0.26 to 1.50)

0.40

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VariableInduction

group(n=1333)


group(n=1351)



Sepsis 9/1333 (0.7%) 20/1346 (1.5%) 0.46 (0.21 to 1.00)

0.065

Exploratory neonatal outcome variablesDays at neonatal intensive care units (NICU)

3.38 (2.97)2

(1; 6)n=55

4.59 (5.64)3

(1; 6)n=81‡

0.15 -1.21 (-2.75 to 0.19)

Admittance to neonatal intensive care units (NICU) >4 days

34/55 (61.8%) 45/81 (55.6%) 1.11 (0.84 to 1.48)

0.58

Hypoglycaemia§ 22/1333 (1.7%) 20/1346 (1.5%) 1.11 (0.61 to 2.03)

0.84

Birth trauma¶ 0/1333 (0.0%) 1/1346 (0.1%) 1.00

Small for gestational age (SGA)** 9/1333 (0.7%) 21/1351 (1.6%) 0.43 (0.20 to 0.94)

0.045

Large for gestational age (LGA)** 20/1333 (1.5%) 24/1351 (1.8%) 0.84 (0.47 to 1.52)

0.68

Any major birth defect†† 14/1333 (1.1%) 17/1351 (1.3%) 0.83 (0.41 to 1.69)

0.75

Female 576/1333 (43.2%)

612/1351 (45.3%)

0.95 (0.88 to 1.04)

0.29

CI=confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presented.For comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables Fisher´s Exact test (2-sided) was used for dichotomous variables and Fisher´s Non-Parametric Permutation test was used for continuous variables. *Apgar score of live births†validated umbilical cord samples defined as values of arterial pH < venous pH and values of arterial pCO2 >venous pCO2‡one infant with only home based neonatal care§hypoglycaemia defined as P-glucose concentration < 2,6 mmol/L after 3 hours¶defined as any of long bone fracture, clavicular fracture, skull fracture, other neurological injury, retinal haemorrhage, facial nerve palsy**SGA and LGA defined as <-2 SD and >2 SD, respectively, according to the Swedish sex specific reference17

††minor birth defects according to EUROCAT definition excluded21

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Supplementary Table F Maternal adverse outcomes in per protocol population



group(n=1351)


Secondary maternal outcomesChorioamnionitis 2/1333 (0.2%) 6/1351 (0.4%) 0.34 (0.07 to 1.67) 0.30

Shoulder dystocia 6/1333 (0.5%) 4/1351 (0.3%) 1.52 (0.43 to 5.38) 0.74

Perineal lacerations III-IV 35/1333 (2.6%) 50/1351 (3.7%) 0.71 (0.46 to 1.09) 0.14

Postpartum haemorrhage (>1000 ml) 134/1333 (10.1%) 143/1351 (10.6%) 0.95 (0.76 to 1.19) 0.70

Wound infection 4/1333 (0.3%) 3/1351 (0.2%) 1.35 (0.30 to 6.03) 0.99

Urinary tract infection incl. pyelonephritis

5/1333 (0.4%) 7/1351 (0.5%) 0.72 (0.23 to 2.28) 0.79

Endometritis 17/1333 (1.3%) 5/1351 (0.4%) 3.45 (1.27 to 9.31) 0.015

Sepsis 0/1333 (0.0%) 0/1351 (0.0%) 1.00

Exploratory maternal outcomesPreeclampsia/gestational hypertension/eclampsia

17/1333 (1.3%) 41/1351 (3.0%) 0.42 (0.24 to 0.74) 0.002

Uterine rupture 0/1333 (0.0%) 0/1351 (0.0%) 1.00

Cervical laceration 5/1333 (0.4%) 8/1351 (0.6%) 0.63 (0.21 to 1.93) 0.60

Venous thromboembolism 0/1333 (0.0%) 1/1351 (0.1%) 1.00

Maternal admission to intensive care unit

2/1333 (0.2%) 0/1351 (0.0%) 0.49

Maternal death 0/1333 (0.0%) 0/1351 (0.0%) 1.00CI= confidence intervalFor categorical variables n/N (%) is presented.For continuous variables Mean (standard deviation [SD]) / Median interquartile range [IQR] Q1; Q3) / n= is presented.For comparison between groups Fisher´s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables and Fisher´sNon-Parametric Permutation test was used for continuous variables

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BMJ · Confidential: For Review Only Induction of labour at 41 weeks versus expectant management until 42 weeks (the Swedish postterm induction study - SWEPIS), a multicentre, open