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Induction of labor at full term in uncomplicated singleton gestations: a systematic review and metaanalysis of randomized controlled trials

AJOG Volume 213, Issue 5, November 2015, Pages 629–636

Editor’s comment: Prof. Dan Farine: Another meta-analysis that changes dogmas in obstetrics
This is another meta-analysis that changes dogmas in obstetrics.  The common wisdom has been that induction of labor increases the risk of cesarean delivery and the risk is higher if the cervix is unripe. This started changing with the post-term trial of Mary Hannah that showed that at 41 weeks there is better outcome with induction of labor. This is the third meta-analysis showing that induction of labor at term and post term does not increase the risk of CS and results in a better outcome for the baby. It has been known for long time that the rate of stillbirth starts increasing at 38 weeks on a weekly basis. This new sets of data allows for an earlier induction of labor without worrying  about poor outcome and increased cesareans. The meta-anlysis by Mishanina E et al. in the CMAJ may explain why the new data is different from the old dogma as they show that oxytocin only induction does not offer these benefits (and neither do preterm inductions).  This information is even more important as the number of pregnancies in older women is increasing. There is ample data now showing that risk of stillbirths at women that are 40 years and older at 39 weeks is similar to that of younger women at  41 weeks. These women can now be induced at 39 weeks without worrying about the induction per se increasing their CS rate.

The aim of this study was to evaluate the risk of cesarean and any maternal and perinatal effects of a policy induction of labor in uncomplicated full-term singleton gestations. Searches were performed in an electronic database with the use of a combination of text words related to “induction” and “cesarean section” from inception of each database through December 2014. We included all randomized controlled trials of uncomplicated singleton gestations at full term (ie, between 39 weeks 0/7 days and 40 weeks 6/7 days) with intact membranes randomized to induction of labor or control (ie, expectant management). The primary outcome was the incidence of cesarean delivery. The summary measures were reported as risk ratio (RR) with 95% confidence interval (CI). Five randomized controlled trials, including 844 women, were analyzed. Full-term vertex singleton gestations receiving induction of labor had similar incidence of cesarean delivery compared to controls (9.7% vs 7.5%; RR, 1.25; 95% CI, 0.75–2.08). Rates of spontaneous (75.9% vs 80.2%; RR, 0.95; 95% CI, 0.87–1.02) and operative (13.1% vs 10.6%; RR, 1.22; 95% CI, 0.83–1.81) vaginal delivery were also similar. Induction was associated with similar rates of chorioamnionitis (9.6% vs 8.0%; RR, 1.17; 95% CI, 0.38–3.39), but statistically significantly less blood loss (mean difference –57.59 mL; 95% CI, –83.96 to –31.21) compared to controls. Regarding neonatal outcomes, induction was associated with a significantly lower rate of meconium-stained amniotic fluid (4.0% vs 13.5%; RR, 0.32; 95% CI, 0.18–0.57) and significantly lower mean birthweight (mean difference –135.51 g; 95% CI, –205.24 to –65.77) compared to control group. Induction of labor at full term in uncomplicated singleton gestations is not associated with increased risk of cesarean delivery and has overall similar outcomes compared to expectant management.

Key words: cesarean delivery, induction, labor.

Data have shown that the lowest incidence of perinatal morbidity and mortality occurs around 39-40 weeks. As perinatal morbidity and mortality rates are higher during the early-term period (370-386 weeks) compared with those delivered at ≥39 weeks, the American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have recommended against nonmedically indicated deliveries <39 weeks. Instead, perinatal mortality starts to increase again with late term (410-416 weeks) and postterm (≥42 weeks) pregnancies.

Therefore, some have advocated induction of even uncomplicated singleton gestations once they reach full term (390-406 weeks).4, 5, 6, 7, and 8 Opponents of such a policy have remarked that induction has often been associated in observational studies with an increased risk of cesarean delivery.9, 10, 11, and 12 Recently though, several randomized controlled trials (RCTs) of term or near-term pregnancies with indications for induction have shown that induction is not associated with an increased risk of cesarean, and is instead associated with some maternal and perinatal benefits.13, 14, and 15

The aim of this study was to evaluate the risk of cesarean and any maternal and perinatal effects of a policy induction of labor in full-term asymptomatic and uncomplicated singleton gestations.

Materials and Methods

Eligibility criteria

The research protocol was designed a priori. We performed electronic research in OVID (ie, LWW Health Library and Maternity and Infant Care), Scopus, ClinicalTrials.gov , MEDLINE, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, and the Cochrane Central Register of Controlled Trials with the use of a combination of text words related to “induction,” “cesarean section,” “cesarean,” “expectant management,” and “pregnancy” from inception of each database through December 2014. All results were then limited to “clinical trial.” No restrictions for language or geographic location were applied.

Study selection

We included all RCTs of asymptomatic and uncomplicated singleton gestations at full term (ie, between 390 and 406 weeks) with intact membranes randomized to induction of labor or control (ie, expectant management).

Only trials on asymptomatic singleton gestations without premature rupture of membranes or any other indications for induction evaluating the efficacy of induction of labor in full-term singleton gestations were included. Exclusion criteria included quasirandomized trials, and trials in women with premature rupture of membranes, with indication for induction (ie, intrauterine growth restriction, diabetes, gestational hypertension/preeclampsia, oligohydramnios, fetal macrosomia), and with multiple gestations.

The metaanalysis was reported following the Preferred Reporting Item for Systematic Reviews and Metaanalyses (PRISMA) statement. Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration no. CRD42014014261).

Data abstraction

Data abstraction was completed by 2 independent investigators (G.S., V.B.). Each investigator independently abstracted data from each study and analyzed data separately. All analyses were done using an intention-to-treat approach, evaluating women according to the treatment group to which they were randomly allocated in the original trials. The primary outcome was the incidence of cesarean delivery. Secondary outcome included spontaneous vaginal delivery, operative vaginal delivery (forceps or vacuum), chorioamnionitis, postpartum blood loss, and neonatal outcomes including meconium-stained amniotic fluid (MSAF), Apgar score <7 at 5 minutes, birthweight, admission to neonatal intensive care unit (NICU), and perinatal death. For studies that did not stratify data, composite data were extracted. All authors were contacted for missing data. We planned subgroup analyses in women with favorable cervix, in nulliparous women only, in women who received induction between 390 and 396, and in women with a previous cesarean delivery.

The risk of bias in each included study was assessed by using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.

Data analysis

The data analysis was completed independently by the authors using Review Manager 5.3 (2014; The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). The completed analyses were then compared, and any difference was resolved with review of the entire data. Statistical heterogeneity between studies was assessed using the Cochrane Q statistics and Higgins I2 statistics. In case of statistically significant heterogeneity, the random effects model of DerSimonian and Laird was used to obtain the pooled risk ratio (RR) estimate, otherwise a fixed effect model was planned. The summary measures were reported as RR with 95% confidence interval (CI). P value < .05 was considered statistically significant. This study had no funding source.

Results

Study selection and study characteristics

We initially identified 16 RCTs evaluating the efficacy of induction in full-term gestations.4, 5, 6, 7, 8, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, and 25 Eleven studies were excluded.13, 14, 15, 18, 19, 20, 21, 22, 23, 24, and 25 Five RCTs that met inclusion criteria for this metaanalysis were analyzed.4, 5, 6, 7, and 8 Figure 1 shows the flow diagram (PRISMA template) of information through the different phases of the review. Two authors provided unpublished data from their trials.7 and 8

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Figure 1 Flow diagram of studies identified in systematic review Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015.

Most studies had a low risk of bias in selective reporting and incomplete outcome data according with the Cochrane Collaboration tool. No study was double-blind because this was deemed difficult methodologically given the intervention ( Figure 2 ).

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Figure 2 Assessment of risk of bias A, Summary of risk of bias for each trial. B, Risk of bias graph about each risk of bias item presented as percentages across all included studies. +, low risk of bias; , high risk of bias; ?, unclear risk of bias. Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015. source: Cole ; Martin ; Tylleskar ; Nielsen ; Miller.

The characteristics of the 5 included trials are summarized in Table 1 . Of the 884 women, 444 (50%) were randomized to induction group and 440 (50%) to control. All studies enrolled only uncomplicated full-term vertex singleton gestations.4, 5, 6, 7, and 8 Two studies enrolled only women with favorable cervix defined as a Bishop score of ≥5 in nulliparous or ≥4 in multiparous patients.6 and 7 Only 1 study reported separate data in nulliparous and multiparous women. No studies reported data about prior cesarean delivery.

Table 1 Characteristics of included studies

Characteristic Cole et al, 1975 Martin et al, 1978 Tylleskar et al, 1979 Nielsen et al, 2005 Miller et al, 2014
Location United Kingdom United Kingdom Sweden United States United States
Sample size, n (induction/control) 228 (111/117) 184 (92/92) 84 (43/41) 226 (116/110) 162 (82/80)
Inclusion criteria Singleton, uncomplicated Singleton, uncomplicated Singleton, uncomplicated, favorable cervix Singleton, uncomplicated, favorable cervix Singleton, uncomplicated, nulliparous, unfavorable cervix
Range GA at randomization, wk 390–406 380–386 400–406 380–386 380–386
Range GA at induction, wk 390–406 390–396 400–406 390–396 390–396
Induction method AROM, oxytocin AROM, oxytocin AROM, oxytocin AROM, oxytocin Misoprostol followed by Foley bulb and oxytocin, or Foley bulb and oxytocin
Control group Expectant management and possible induction at 41 wk Expectant management and possible induction at 42 wk Expectant management Expectant management and possible induction at 42 wk Expectant management
Study primary outcomes Meconium staining Serum bilirubin levels, meconium staining N/R Cesarean delivery Cesarean delivery

AROM, artificial rupture of membranes; GA, gestational age; N/R, not reported.

Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015.

Synthesis of results

Uncomplicated full-term singleton gestations receiving induction of labor had similar incidence of cesarean delivery compared to controls (9.7% vs 7.5%; RR, 1.25; 95% CI, 0.75–2.08) ( Figure 3 and Table 2 ). Rates of spontaneous (75.9% vs 80.2%; RR, 0.95; 95% CI, 0.87–1.02) and operative (13.1% vs 10.6%; RR, 1.22; 95% CI, 0.83–1.81) vaginal delivery were also similar. Induction was associated with similar rates of chorioamnionitis (9.6% vs 8.0%; RR, 1.17; 95% CI, 0.38–3.39), but significantly less blood loss (mean difference –57.59 mL; 95% CI, –83.96 to –31.21) ( Figure 4 ) compared to controls. Regarding neonatal outcomes, induction was associated with a significantly lower rate of MSAF (4.0% vs 13.5%; RR, 0.32; 95% CI, 0.18–0.57) ( Figure 5 and Table 2 ), and significantly lower mean birthweight (mean difference –135.51 g; 95% CI, –205.24 to –65.77) compared to control group. There were no differences in other adverse neonatal outcomes, including Apgar <7 at 5 minutes, NICU admission, and perinatal death, between the 2 groups ( Table 2 ).

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Figure 3 Forest plot for cesarean delivery CD, cesarean delivery; CI, confidence interval; M-H, Mantel-Haenszel. Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015. source: Cole ; Martin ; Tylleskar ; Nielsen ; Miller.

Table 2 Primary and secondary outcomes of included studies

Variable Cole et al, 1975 Martin et al, 1978 Tylleskar et al, 1979 Nielsen et al, 2005 Miller et al, 2014 Total RR (95% CI)
Cesarean delivery 5/111 (4.5%) vs 9/117 (7.7%) 4/92 (4.3%) vs 1/92 (1.1%) 1/43 (2.3%) vs 1/41 (2.4%) 8/116 (6.7%) vs 8/110 (7.8%) 25/82 (30.5%) vs 14/80 (17.5%) 43/444 (9.7%) vs 33/440 (7.5%) 1.25 (0.75–2.08)
SVD 72/111 (64.7%) vs 82/117 (70.1%) N/R 41/43 (95%) vs 38/41 (92.7%) 100/116 (86.2%) vs 93/110 (84.5%) 54/82 (65.9%) vs 66/80 (82.5%) 267/352 (75.9%) vs 279/348 (80.2%) 0.95 (0.87–1.02)
Operative vaginal delivery 34/111 (30.6%) vs 26/117 (22.2%) N/R 1/43 (2.3%) vs 2/41 (4.9%) 8/116 (6.9%) vs 9/110 (8.2%) 3/82 (3.7%) vs 0/80 46/352 (13.1%) vs 37/348 (10.6%) 1.22 (0.83–1.81)
Chorioamnionitis N/R N/R N/R 7/116 (6.0%) vs 6/110 (5.5%) 12/82 (14.6%) vs 9/80 (11.3%) 19/198 (9.6%) vs 15/190 (8.0%) 1.17 (0.38–3.39)
Mean blood loss, mL 185 vs 233 N/R N/R 303 vs 312 754 vs 900 Mean difference –57.59 mL (–83.96 to –31.21)
Meconium-stained amniotic fluid 1/111 (0.9%) vs 13/117 (11.1%) 3/92 (3.3%) vs 13/92 (14.1%) N/R 6/116 (5.2%) vs 11/110 (10%) 6/82 (7.3%) vs 17/80 (21.3%) 16/401 (4.0%) vs 54/399 (13.5%) 0.32 (0.18–0.57)
Apgar <7 at 5 min N/R N/R N/R 0/116 vs 0/110 0/82 vs 1/80 0/198 (0%) vs 1/190 (0.5%) 0.33 (0.01–7.87)
Mean birthweight, g 3250 vs 3390 N/A 3638 vs 3720 3459 vs 3604 3401 vs 3513 Mean difference –135.51 (–205.24 to –65.77)
NICU admission N/R N/R N/R 0/116 vs 0/110 5/82 (6.1%) vs 5/80 (6.3%) 5/198 (3.0%) vs 5/190 (2.6%) 0.98 (0.47–2.04)
Perinatal death 0/111 vs 1/117 (0.9%) 0/92 vs 1/92 (1.1%) N/R 0/116 vs 0/110 0/82 vs 0/80 0/401 (0%) vs 2/399 (0.5%) 0.35 (0.04–3.37)

a Forces or vacuum

b Statistically significant.

Data are presented as n induction vs n control (percentage).

CI, confidence interval; NICU, neonatal intensive care unit; N/R, not reported; RR, risk ratio; SVD, spontaneous vaginal delivery.

Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015.

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Figure 4 Forest plot for blood loss CI, confidence interval. Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015. source: Cole ; Nielsen ; Miller.

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Figure 5 Forest plot for meconium-stained amniotic fluid CI, confidence interval; M-H, Mantel-Haenszel; MSAF, meconium-stained amniotic fluid. Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015. source: Cole ; Martin ; Nielsen ; Miller.

Table 3 shows the results for primary outcome in the subgroup analyses. We found no differences in the rate of cesarean delivery in women with favorable cervix, in nulliparous women, and in women who received induction between 390 and 396 weeks ( Table 3 ). No study stratified data by previous cesarean delivery. Since no studies stratified data for multiparous women with favorable cervices, this subgroup analysis was not feasible.

Table 3 Primary outcome (incidence of cesarean delivery) in subgroup analyses

Population Outcome Included studies Total RR (95% CI)
Favorable cervix Cesarean delivery Tyllerskar 1979

Nielsen 2005
9/159 (5.7%) vs 9/151 (6.0%) 0.95 (0.39–2.32)
Nulliparous women Cesarean delivery Tylleskar 1979

Miller 2014
26/102 (25.5%) vs 15/98 (15.3%) 1.67 (0.94–2.95)
Induction 390–396 Cesarean delivery Martin 1978

Nielsen 2005

Miller 2014
37/290 (12.8%) vs 23/282 (8.2%) 1.55 (0.96–2.51)

CI, confidence interval; RR, risk ratio.

Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015.

Comment

Main findings

This metaanalysis of the 5 RCTs evaluating full-term (390-406 weeks) uncomplicated vertex singleton gestations shows that induction of labor is not associated with an increased risk of cesarean delivery compared to controls expectantly managed at least until ≥41 weeks. Furthermore, induction of labor was associated with a significantly lower blood loss, albeit of only 58 mL, and significantly lower rate of MSAF. Although induction was associated with lower birthweight, a mean difference of about 136 g at full term is probably not clinically significant, and we found no differences in adverse neonatal outcomes, including Apgar <7 at 5 minutes, NICU, and perinatal death, between intervention and control groups.

Comparison with existing literature

Two other metaanalyses have addressed induction of labor and cesarean delivery.26 and 27 Both included women with indications for induction, such as intrauterine growth restriction, hypertensive complications, or ≥41 weeks.26 and 27 Both showed not only no increase in cesarean delivery, but in fact a significant decrease in the incidence of cesarean. However, there were concerns about the translation of these findings into actual practice due to a type II error and due to a high heterogeneity between the studies, thus both reviews called for future research.26 and 27 Another recent review showed that the risk of cesarean delivery was lower among women whose labor was induced than among those managed expectantly in term and postterm gestations. That study included all RCTs in women at near term, early term, full term, and postterm with and without medical indication for induction. Instead, we included only women at full term with no medical indication for induction. No other prior metaanalysis included only full-term singleton uncomplicated pregnancies without indications for induction.

Some have referred to inductions without an indication at term as “elective,” but we prefer avoiding the use of this term, as it lacks as the necessary scientific specificity. We instead prefer to always document the specific indication (whether medical or nonmedical) for the intervention or procedure. In this case, “induction for full-term gestation” could be used. If no indication is present, the term “elective” should still be avoided, and instead “nonmedically indicated induction” could be used.

Strengths and limitations

One of the strengths of our study is the inclusion of RCT data on induction of pregnancy in a specific population, ie, asymptomatic and uncomplicated singletons at full term. Furthermore, most of the included RCTs were at low risk of bias according to the Cochrane risk of bias tool, and the number of women analyzed was high. The risk of publication bias was assessed by visual inspection of funnel plot and the symmetric plot suggested no publication bias ( Figure 6 ). Two authors provided additional data from their trials.7 and 8 Our study included both nulliparous and multiparous women, and we performed in addition a subgroup analysis in only nulliparous women.

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Figure 6 Funnel plot assessing publication bias RR, risk ratio. Saccone. Induction of labor at full term. Am J Obstet Gynecol 2015.

Limitations of our study are inherent to the limitations of the included RCTs. Only 2 of the included RCTs had cesarean delivery as primary outcome. No long-term outcomes were reported in any of the trials. The overall rate of cesarean is slightly less than expected, and this raises the question of external generalizability to the current US population. Even with a summary estimate from 5 well-designed RCTs, the ability to discern differences in important clinical outcomes was impaired by a type II error. The number of included women in subgroup analyses was low, and so these comparisons were underpowered. This may be particularly important to point out for the nulliparous population (n = 200), where there is the most controversy regarding induction without medical indication ( Table 3 ).

Conclusions and implications

Induction of labor in asymptomatic and uncomplicated singleton gestations at full term (390-406 weeks) is not associated with increased risk of cesarean delivery and has overall similar outcomes compared to expectant management, with some significant maternal (less blood loss) and perinatal (lower risk of MSAF) benefits. MSAF is associated with an increased risk of adverse fetal outcomes including meconium aspiration syndrome (MAS), cerebral palsy, seizure, and pulmonary disease.30, 31, and 32 MAS occurs in 5% of the cases of MSAF and >4% of infants with MAS die, accounting for 2% of perinatal deaths.33 and 34 Furthermore, earlier delivery is associated with higher women’s satisfaction. However, given the limitations of power, a firm conclusion could not be drawn.

Larger properly powered trials are needed, particularly in nulliparous women. We observed that with an α of 0.05 and 80% power, a sample size of 2000 women is required to detect an increase in cesarean from 7.5-9.7%. We eagerly await results of the ongoing Eunice Kennedy Shriver National Institute of Child Health and Human Development trial.

Acknowledgments

We thank Dr Nielsen and Dr Miller for providing additional unpublished data from their trials.

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Footnotes

a Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy

b Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA

Corresponding author: Vincenzo Berghella, MD.

The authors report no conflict of interest.