Induction of Labor and Risk of Postpartum Hemorrhage in Low Risk Parturients
Induction of Labor and Risk of Postpartum Hemorrhage in Low Risk Parturients
Induction of Labor and Risk of Postpartum Hemorrhage in Low Risk Parturients
Abstract
Objective: Labor induction is an increasingly common procedure, even among women at low risk, although evidence to
assess its risks remains sparse. Our objective was to assess the association between induction of labor and postpartum
hemorrhage (PPH) in low-risk parturients, globally and according to its indications and methods.
Method: Population-based case-control study of low-risk women who gave birth in 106 French maternity units between
December 2004 and November 2006, including 4450 women with PPH, 1125 of them severe, and 1744 controls. Indications
for labor induction were standard or non-standard, according to national guidelines. Induction methods were oxytocin or
prostaglandins. Multilevel multivariable logistic regression modelling was used to test the independent association between
induction and PPH, quantified as odds ratios.
Results: After adjustment for all potential confounders, labor induction was associated with a significantly higher risk of PPH
(adjusted odds ratio, AOR1.22, 95%CI 1.041.42). This excess risk was found for induction with both oxytocin (AOR 1.52,
95%CI 1.191.93 for all and 1.57, 95%CI 1.112.20 for severe PPH) and prostaglandins (AOR 1.21, 95%CI 0.971.51 for all and
1.42, 95%CI 1.041.94 for severe PPH). Standard indicated induction was significantly associated with PPH (AOR1.28, 95%CI
1.061.55) while no significant association was found for non-standard indicated inductions.
Conclusion: Even in low risk women, induction of labor, regardless of the method used, is associated with a higher risk of
PPH than spontaneous labor. However, there was no excess risk of PPH in women who underwent induction of labor for
non-standard indications. This raises the hypothesis that the higher risk of PPH associated with labor induction may be
limited to unfavorable obstetrical situations.
Citation: Khireddine I, Le Ray C, Dupont C, Rudigoz R-C, Bouvier-Colle M-H, et al. (2013) Induction of Labor and Risk of Postpartum Hemorrhage in Low Risk
Parturients. PLoS ONE 8(1): e54858. doi:10.1371/journal.pone.0054858
Editor: Shannon M. Hawkins, Baylor College of Medicine, United States of America
Received August 3, 2012; Accepted December 17, 2012; Published January 25, 2013
Copyright: 2013 Khireddine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The project was funded by the French Ministry of Health under its Clinical Research Hospital Program (contract no.27-35) and the Caisse Nationale
dAssurance Maladie (CNAMTS). IK was supported by a grant from lInstitut de Recherche en Sante Publique (IRESP). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected] (CDT)
Introduction
In most developed countries, induction of labor is an
increasingly common obstetric procedure [13]. It has been
medically indicated for decades in women at high risk to prevent
the risks associated with the prolongation of pregnancy and
national guidelines listing these indications have been established
[46]. In these situations, it has been associated with improved
maternal and neonatal health outcomes [710]. The issue is
different for low-risk women, most of whom are expected to start
labor spontaneously, without needing medical induction. Several
reports have shown, however, that labor induction has also
become a common procedure in this group and that its use has
been extended to non-standard indications or even reasons of
convenience [1116]. This trend is of particular concern because
evidence regarding the potential risks associated with induction is
lacked the power to detect a difference between the two groups for
this outcome.
Our objective was to study the association between induction of
labor and PPH in women at low risk, according to its methods and
indications.
Methods
We conducted a population-based cohort-nested casecontrol study
The study population included women selected from the
Pithagore6 trial population [24]. This cluster-randomized controlled trial was conducted between December 2004 and
November 2006 in 106 French maternity units of three French
regions representing 17% of all French maternity units and
covering 20% of deliveries nationwide. Its main objective was to
evaluate a multifaceted intervention for reducing the rate of severe
PPH. No significant difference in the rate of severe PPH was found
between the group of units who received the intervention and the
reference group of units where no intervention was conducted (see
reference for full description of the original study [24].
PPH was clinically defined as an estimated blood loss greater
than 500 mL within the first 24 hours after the birth. Birth
attendants in each unit prospectively identified all deliveries with
PPH and reported them to the research team. In addition, a
research assistant reviewed the delivery suite logbook of each unit
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Results
Of the 1744 low-risk women in the control group, labor was
induced for 316 (18.1%). Among the latter, the indication was
standard for 196 (62.0%) and non-standard for 120 (38.0%)
(Table 1). The primary standard indications were post term
pregnancy in 150 (76.5%) women, and premature rupture of
membranes in 35 (17.8%) women. Non-standard indications were
most often convenience inductions or inductions with no specified
indication in 81 (67.5%) women (Table 1). The method of
induction varied with the indication; in standard indications, the
main method used was cervical ripening in 123 (62.8%) women,
whereas oxytocin was mainly used for nonstandard inductions in
70 (58.3%) of women (p,0.01 for x2 test).
Neither the proportion of women with induced labor nor the
indications and methods of induction varied significantly by the
characteristics of the maternity units (status - university, other
public, or private - and annual number of deliveries) (data not
shown).
The bivariate analysis shows that labor was induced more often
among women with PPH and severe PPH than among the
controls (p,0.01) (Table 2). Cases and controls also differed
significantly when considering the indications (p,0.01) and
methods of labor induction (p,0.01) (Table2). The mean total
dose of oxytocin received during labor was significantly greater
among PPH cases than among the controls 1.52 +/2 0.04 and
0.95 +/2 0.06 UI, p ,0.01 for Kruskall Wallis test); and greater
among induced women than in women with spontaneous onset of
labor, among both cases (3.05 +/2 0.09 and 1.10 +/2 0.03 UI
respectively, p,0.01 for Kruskall Wallis test) and controls (2.04 +/
2 0.13 and 0.71 +/2 0.13 UI respectively, p,0.01 for Kruskall
Wallis test). Other characteristics that were more common among
case women were: maternal age,25 years, primiparity, postterm
pregnancy, epidural analgesia, prolonged active phase of labor,
instrumental vaginal delivery, episiotomy, macrosomia and the
absence of prophylactic oxytocin in the third stage of labor
(Table 2). After adjustment for maternal, labor and delivery
characteristics in the multivariate analysis, induced labor was
3
%*
196
(62.0)
150
76.5
35
17.8
18
9.2
Oligoamnios
4.1
3.1
2.5
1.0
120
(38.0)
81
67.5
11
9.2
10
8.3
6.7
Placental calcification
3.3
Isolated edema
2.5
Isolated proteinuria
1.6
Isolated hyperuricemia
1.6
Others**
6.7
Total
n (%)
316 (100)
Discussion
We found that induction of labor was independently associated
with a 20 % higher risk of PPH and severe PPH in low-risk
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Table 2. Characteristics of women, labor and delivery in women with PPH, severe PPH and in control women.
Controls
Induced labor
PPH cases
P**
N = 1744
N = 4477
N = 1125
n (%)*
n (%)*
n (%)*
316 (18.1)
964 (21.5)
,.01
245 (21.8)
,.01
185 (16.4)
P***
0.01
1428 (81.9)
3513 (78.5)
196 (11.2)
663 (14.8)
120 (6.8)
301 (6.7)
880 (78.2)
,.01
60 (5.3)
607 (34.9)
1258 (28.2)
274 (24.4)
818 (47.0)
2247 (50.3)
604 (53.8)
173 (9.9)
521 (11.7)
143 (8.2)
440 (9.8)
,.01
148 (13.2)
,.01
97 (8.6)
268 (15.4)
804 (18.0)
2534
1183 (67.9)
3015 (67.4)
$35
292 (16.7)
653 (14.6)
,25
1172 (80.0)
3127 (79.3)
2529
220 (15.0)
572 (14.5)
$30
74 (5.0)
241 (6.2)
210 (18.7)
0.01
767 (68.2)
,.01
147 (13.1)
BMI (kg/m2)
Missing data
278 (16){
537 (12.0){
Primiparity
809 (46.4)
2678 (59.8)
803 (80.9)
0.31
138 (13.9)
0.74
52 (5.2)
132 (11.7){
,.01
786 (69.9)
,.01
645 (57.4)
,.01
357 (20.5)
646 (14.4)
3940
1058 (60.7)
2649 (59.3)
$41
328 (18.8)
1175 (26.3)
Epidural analgesia
1297 (74.4)
3568 (79.7)
149 (13.3)
,.01
329 (29.3)
,.01
878 (78.0)
0.02
833 (49.5)
1514 (35.2)
355 (33.4)
[P50P75]
425 (25.3)
1093 (25.4)
238 (22.4)
[P75P90]
262 (15.6)
919 (21.4)
$P90
161 (9.6)
778 (18.0)
228 (21.4)
Missing data
62 (3.6){
173 (3.9){
62 (5.5){
Spontaneous vaginal
1422 (81.5)
3251 (72.6)
Instrumental vaginal
207 (11.9)
955 (21.3)
115 (6.6)
271 (6.1)
,.01
242 (22.8)
,.01
Mode of delivery
697 (62.0)
,.01
321 (28.5)
,.01
107 (9.5)
Episiotomy
551 (31.6)
2027 (45.3)
,.01
611 (54.3)
,.01
Perineal tears
501 (28.7)
1345 (30.0)
0.30
317 (28.2)
0.75
,3000
350 (20.1)
576 (12.9)
30003499
757 (43.4)
1747 (39.1)
35003999
519 (29.8)
1611 (36.0)
$4000
116 (6.7)
539 (12.0)
1253 (71.9)
2609 (58.3)
130 (11.5)
0.31
439 (39.0)
,.01
418 (37.2)
138 (12.3)
,.01
697 (62.0)
,.01
*% of non-missing values
{
% of all women in the group
**chi2 test comparing PPH cases and controls
***chi2 test comparing severe PPH cases and controls
doi:10.1371/journal.pone.0054858.t002
Table 3. Association between induction of labor and risk of PPH and severe PPH in low-risk women, multivariable analyses*
(N = 4477 PPH, 1125 severe PPH and 1744 controls).
Adj OR**
PPH
Adj OR***
Severe PPH
Spontaneous
Ref
Ref
Induced labor
1.22 [1.041.42]
1.20 [0.971.48]
Onset of labor
Ref
Ref
1.28 [1.061.55]
1.33 [1.041.71]
1.11 [0.891.40]
0.96 [0.681.36]
Ref
Ref
1.17 [1.001.37]
1.35 [1.071.70]
1.21 [0.971.51]
1.42 [1.041.94]
1.52 [1.191.93]
1. 57 [1.112.20]
Bishop scores were not available in this study, most of the standard
inductions were performed by cervical ripening, in contrast to non
standard indications, and thus suggests that these women are more
likely to have an unfavorable cervix. Prolonged active phase of
laboran independent risk factor for postpartum hemorrhage
[32,33]may be more common in women with unfavorable cervix,
and explain the association between standard induction and PPH;
however, the fact that this association remains significant when we
Table 4. Association between induction of labor and risk of PPH and severe PPH among low-risk primiparas, multivariable
analyses*.
Controls
N = 809
n (%)
PPH cases
N = 2678
n (%)
Adj OR**
P value PPH
,.01
Onset of labor
Spontaneous (ref)
657 (81.2)
2076 (77.5)
Induced labor
152 (18.8)
602 (22.5)
Ref
612 (77.9)
1.27 [1.031.58]
174 (22.1)
0.02
Ref
1.22 [0.931.61]
657 (81.2)
2076 (77.5)
108 (13.4)
440 (16.4)
44 (5.4)
162 (6.1)
,.01
Ref
612 (77.8)
1.35 [1.041.74]
142 (18.1)
1.13 [0.801.60]
32 (4.1)
Ref
,.01
1.43 [1.041.97]
0.79 [0.481.29]
196 (24.3)
499 (18.7)
460 (56.9)
1571 (58.8)
Ref
136 (17.3)
1.18 [0.931.50]
475 (60.5)
97 (12.0)
396 (14.8)
1.46 [1.062.00]
123 (15.7)
1.71 [1.132.56]
55 (6.8)
205 (7.7)
1.43 [0.982.11]
51 (6.5)
1.35 [0.812.24]
,.01
Ref
,.01
1.39 [1.011.91]
adjusted for the duration of the active phase shows that the effect of
induction on the risk of PPH is not fully mediated by a longer
duration of the active phase of labor. Other specificities of labor
such as long latency phase or need for labor augmentationmay be
more common in women with inductions and unfavorable cervices,
and affect uterine contractility in the immediate postpartum period.
In our study, the great majority of standard indicated inductions
were performed for post-term deliveries. This raises the issue of the
causal implication of this condition in the development of
subsequent PPH, although there is no clear physiological hypothesis
supporting the existence of such a direct impact. The independent
role of a late gestational age at delivery on the risk of PPH could not
be properly investigated here because of the rarity of other standard
indications for induction; future research should focus on the role of
late gestational age in the risk of PPH. Finally, we cannot exclude
that a weak but significant association exists between induction for
non standard indications and PPH, but that the power available was
insufficient to detect it; however, this explanation seems unlikely
because the numbers of cases and controls still provide an adequate
power for a strength of association of 1.3 or more, and the estimates
for the odds ratios were very closed to 1.
Even in low risk women, induction of labor, regardless of the
method used, is associated with a higher risk of PPH than
Acknowledgments
The authors want to thank the staff from the participating maternity units
for identifying cases, and Francois Goffinet for his comments on the
manuscript.
Author Contributions
Conceived and designed the experiments: CLR CD RCR MHBC CDT.
Performed the experiments: CD CDT. Analyzed the data: IK CLR CDT.
Wrote the paper: IK CLR CD RCR MHBC CDT.
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