Preventive Medicine Reports 40 (2024) 102665

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Preventive Medicine Reports

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Severe postpartum hemorrhage and the risk of adverse maternal outcome:

A comparative analysis of two population-based studies in France and
the Netherlands
P.L.M. de Vries a, b, *, C. Deneux-Tharaux c, C. Caram-Deelder d, F. Goffinet b, c,
D.D.C.A. Henriquez d, A. Seco e, J.G. van der Bom d, T. van den Akker a, f
a
Department of Obstetrics, Leiden University Medical Centre, Leiden, The Netherlands
b
Port-Royal Maternity Unit, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
c
Université Paris Cité, Inserm, Obstetrical, Perinatal and Paediatric Epidemiology Research Team (Epopé), CRESS UMR 1153, Paris, France
d
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
e
Clinical Research Unit Necker Cochin, APHP, Paris, France
f
Athena Institute, VU University, Amsterdam, The Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: Among women with severe PPH (sPPH) in France and the Netherlands, we compared incidence of
Cross-country studies adverse maternal outcome (major obstetric hemorrhage (≥2.5L blood loss) and/or hysterectomy and/or mor­
Obstetric hemorrhage tality) by mode of delivery. Second, we compared use and timing of resuscitation and transfusion management,
Management
second-line uterotonics and uterine-sparing interventions (intra-uterine tamponade, compression sutures,
Clinical care
Severe maternal outcome
vascular ligation, arterial embolization) by mode of delivery.
Maternal mortality Methods: Secondary analysis of two population-based studies of women with sPPH in France and the
Maternal morbidity Netherlands. Women were selected by a harmonized definition for sPPH: (total blood loss ≥ 1500 ml) AND
(blood transfusion of ≥ 4 units packed red blood cells and/or multicomponent blood transfusion).
Findings: Incidence of adverse maternal outcome after vaginal birth was 793/1002, 9.1 % in the Netherlands
versus 88/214, 41.1 % in France and 259/342, 76.2% versus 160/270, 59.3% after cesarean. Hemostatic agents
such as fibrinogen were administered less frequently (p < 0.001) in the Netherlands (vaginal birth: 83/1002,
8.3% versus 105/2014, 49.5% in France; cesarean: 47/342, 13.7% and 152/270, 55.6%). Second-line utero­
tonics were started significantly later after PPH-onset in the Netherlands than France (vaginal birth: 46 versus 25
min; cesarean: 45 versus 18 min). Uterine-sparing interventions were less frequently (p < 0.001) applied in the
Netherlands after vaginal birth (394/1002,39.3 %, 134/214, 62.6%) and cesarean (133/342, 38.9 % and 155/
270, 57.4%), all initiated later after onset of refractory PPH in the Netherlands.
Interpretation: Incidence of adverse maternal outcome was higher among women with sPPH in the Netherlands
than France regardless mode of birth. Possible explanatory mechanisms are earlier and more frequent use of
second-line uterotonics and uterine-sparing interventions in France compared to the Netherlands.

1. Introduction by individual patient characteristics, differences in mode of delivery or

by different strategies of PPH-prevention and initial PPH-management
Postpartum hemorrhage (PPH) is one of the leading causes of severe between high-income countries (Kallianidis et al., 2021; McCall et al.,
maternal outcomes globally and has recently been on the rise in several 2021). This raises the question whether differences in clinical manage­
high-income countries (Corbetta-Rastelli et al., 2023; Reale et al., 2010; ment of refractory PPH may be involved. Such differences might be
Givens et al., 2022). Between countries of this type, marked variations in compounded by a lack of robust evidence for the management of severe
maternal outcomes after PPH have been reported (Kallianidis et al., PPH and differences in clinical guidance between countries (de Vries
2020; Diguisto and Saucedo, 2022). These are not likely to be explained et al., 2023).

* Corresponding author at: Department of obstetrics, Leiden University Medical Centre. Albinusdreef 2, 2333 AZ, Leiden, The Netherlands.
E-mail address: p.l.m.de_vries@lumc.nl (P.L.M. de Vries).

https://doi.org/10.1016/j.pmedr.2024.102665
Received 26 November 2023; Received in revised form 14 February 2024; Accepted 20 February 2024
Available online 23 February 2024
2211-3355/© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
P.L.M. de Vries et al. Preventive Medicine Reports 40 (2024) 102665

Peripartum hysterectomy is a last-resort management option in case Women in the EpiMOMs study were identified prospectively by care­
of severe PPH. Earlier studies reported a PPH-related maternal mortality givers in participating hospitals and validated by a review of birth log­
ratio and peripartum hysterectomy rate nearly 2-fold as high in France books and registers, hospital discharge databases, and laboratory
as compared to the Netherlands (Kallianidis et al., 2020; Diguisto and records. For both studies, details pertaining to data collection have been
Saucedo, 2022; van den Akker et al.; Ramler et al., 2022; Saucedo and described elsewhere (Siddiqui et al., 2019; Henriquez et al., 2019).
Deneux-Tharaux, 2021). Yet, more than half of PPH-related maternal PPH in France and the Netherlands was managed according to the
deaths in the Netherlands happened in women with the uterus still in national guidelines applicable at the time in both countries (NVOG,
place, suggesting important delay in PPH-management (Ramler et al., 2018; Goffinet et al., 2005). An overview of both guidelines is given in
2022). The importance of timely escalation to more invasive manage­ Table S1.
ment options for PPH has been stressed by several authors (Henriquez Blood loss measurement in the TeMpOH-1 study was obtained by
et al., 2018; Della Torre et al., 2011; Lepine et al., 2020). However, the weighing gauzes, cloths and surgical swabs and by suction canisters or
optimal timing of interventions between the onset of PPH in relation to collector bags in EpiMOMs. Data dictionaries were provided by each
the total amount of blood loss or severe maternal outcome has not been country. If a certain variable was not available, we sought to create a
well defined (Howard and Grobman, 2015). new variable as long as it was comparable in both datasets. If the
Intercountry comparisons of pregnancy outcomes have shown to be equivalent of a variable could not be identified in one of the two data­
useful in revealing suboptimal care by scrutinizing the specificities of bases, it was excluded or presented with a dash. Variables not matching
different national contexts (de Vries et al., 2023). As clinical practice after mapping due to different coding, were subjected to harmonized
and maternal outcome of postpartum hemorrhage varies substantially coding. Availability and comparability of each respective dataset are
between France and the Netherlands, we hypothesized that a compari­ presented in Table S2.
son of the severe PPH-management strategies between these two From both databases, we abstracted variables regarding patient
countries could contribute to a better understanding of optimal PPH- characteristics, etiology of bleeding, initial PPH-management, resusci­
management and the reported differences in terms of severe maternal tation- and transfusion management, second-line uterotonics, obstetric
outcome. management and maternal outcome. Adverse maternal outcome was
The primary outcome of this study was to compare the incidence of defined as a composite of bleeding ≥ 2.5L, hysterectomy or mortality.
adverse maternal outcome, defined as a composite of major obstetric For the subgroup of women with refractory PPH, we assessed the asso­
hemorrhage (≥2.5L of blood loss and/or hysterectomy and/or mortal­ ciation between time of onset of the first uterine-sparing intervention
ity) among women suffering equally severe PPH in France and the (one of the following: intra-uterine balloon tamponade, embolization,
Netherlands by mode of delivery. Second, we aimed to compare use and compression sutures, vascular ligation) and total volume of blood loss. If
timing of resuscitation and transfusion management, second-line ute­ multiple uterine-sparing interventions were performed, time of onset of
rotonics and uterine-sparing interventions between both countries by the first uterine-sparing intervention in the sequence was considered as
mode of delivery. timing of intervention. Patient characteristics were assessed for overall
birth and per mode of delivery. All other variables were stratified by
2. Materials and methods mode of delivery.

2.1. Design 2.4. Statistical analyses

Secondary analysis of two population-based studies. Incidence of severe PPH was calculated per 1,000 births and pre­
sented with a 95 % confidence interval. Data were checked for normal
2.2. Source and study population distribution by histograms. Categorical data were presented by fre­
quency and percentage, and continuous variables by median and
For the Netherlands, data were selected from the TeMpOH-1 study, a interquartile range (25th to 75th percentile) and by mean and standard
nationwide retrospective cohort study of women with severe PPH deviation. Statistical testing by Chi-square tests, T-tests, and kruskall
recruited in 61 hospitals in the Netherlands from January 2011 to Wallis test to test our null-hypothesis that there is no difference between
January 2013. For France, data were extracted from the EpiMOMs the France and the Netherlands with regard to the assessed variables.
study, a population-based prospective study designed specifically to Missing data can be consulted in the supporting information (Table S3).
study severe maternal morbidity in six French regions between May The total volume of blood loss as a function of the timing of the first
2012 and November 2013 that collected data from 119 public and pri­ invasive intervention was displayed in scatterplots. All analyses were
vate maternity units. conducted using STATA v15.
A harmonized definition of severe PPH was applied to select from Ethical approval: The TeMpOH-1 study was approved by the ethics
both studies the broadest common study-population (figure S1). We committee of the Leiden University Medical Center on 31 January 2013
defined severe PPH as: (total blood loss ≥ 1500 ml) and (blood trans­ (P12.273) and by the institutional review board of each participating
fusion of ≥ 4 units of packed red blood cells AND/OR multicomponent hospital. The study was registered in the Netherlands Trial Register
blood transfusion). A multicomponent blood transfusion was defined as (NTR4079). Need to obtain informed consent was waived by the ethics
blood transfusion consisting of a combination of red blood cells and committee. The EpiMOMs study was approved by the appropriate
fresh frozen plasma and/or platelet concentrates. institutional review board, the Commission Nationale de l’Informatique
From this study population, we selected women with ‘refractory et des Libertés (CNIL, number 912210). Need to obtain informed consent
PPH’, which pertained to having severe PPH according to our harmo­ was waived, according to the French legislation at that time. Women
nized definition, and which was refractory to first-line management included in the study were informed and did not indicate their opposi­
(uterine massage, exploration of the uterine cavity, assessment of the tion to participate.
genital tract and administration of oxytocin).
3. Results
2.3. Data collection
3.1. Patient and hemorrhage characteristics
Women in the TeMpOH-1 study were considered eligible for inclu­
sion in the cohort by cross-referencing data from hospitals’ blood In Table 1 we describe the patient characteristics of women sus­
transfusion services with local birth registers in participating hospitals. taining severe PPH in France and the Netherlands. As compared to the

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Table 1
Patient and birth characteristics among women with severe PPH for overall births and stratified by mode of birth in France and the Netherlands (2011–2013).
France The Netherlands

Population based denominator 182,309 207,101

Number of women with sPPH1 484 1344
Incidence sPPH per 1000 births 2.7(2.4–2.9) 5.0 (4.7–5.2)

Overall births Vaginal births Cesarean births

France The Netherlands France The Netherlands France The Netherlands

N= N= P- N= N= P-
214 1002 value 270 342 value

N = 484 N= n (%) n (%) n (%) n (%)

1344

Patient characteristics
Age (Mean (std))2 30.7 (5.1) 31.2 (4.9) 0.15 32.9 (5.5) 33 (5.1) 0,7

Parity 0.07 0,06

nulliparity 210 (43.4) 532 (39.6) 97 (45.5) 428 (42.7) 112 (42.4) 104 (30,4)
multiparous, no 177 (36.6) 621 (42.2) 95 (44.6) 493 (49.2) 82 (53.2) 128 (53.4)
previous cesarean
multiparous with 93 (19.2) 191 (14.2) 21 (9.9) 81 (8.11) 72 (46.8) 110 (46.2)
previous cesarean
History of PPH 27 (10.0) 185 (22.7) 15 (12.9) 144 (25.1) < 12 (7.8) 41 (17.2) <
0,001 0,001
Multiple pregnancy 58 (12.0) 84 (6.3) 14 (6.5) 46 (4.6) 0.26 44 (16.3) 38 (11.1) 0,06
Hypertensive disorder 36 (7.4) 135 (10.0) 9 (4.2) 96 (9.6) 0,01 27 (10.0) 39 (11.4) 0,58
Macrosomia 75 (15.5) 280 (20.8) 35 (16.4) 213 (21.3) 0,11 38 (14.1) 67 (19.6) 0,07
Characteristics of birth
Weeks gestational age 39 (37–41) 39 (38–71) 39 (38–41) 39 0,43 37 (36–68) 37 (35–39) 0,36
(IQR3)
Induction of labor 119 (32.3) 474 (39.6) 68 (31.8) 398 (39.7) 0,06 51 (18.9) 76 (38.9) 0,33
Mode of birth < 0.15
Spontaneous vaginal 152 (31.4) 790 (58.8) 152 (71.0) 790 (78.8) 0.001 - -
birth 62 (12.8) 212 (15.8) 62 (28.9) 212 (21.2) - -
Assisted birth 118 (24.4) 147 (11.0) - - 118 (43.7) 147 (43.0)
Elective cesarean 152 (31.4) 195 (14.5) - - 152 (56.2) 195 (57.0)
Emergency cesarean
Prophylactic 432 (89.3) 1204 (89.6) 198 (92.5) 908 (90.6) 0.38 234 86.6 296 86.6 0.97
uterotonics4
1 2 3 4
= severe postpartum hemorrhage = standard deviation = inter quartile range = Oxyotocin 5 or 10 IU intramuscular or slow intravenous in both countries

Netherlands, more women with severe PPH who gave birth vaginally Netherlands than France after vaginal birth (27/1002,2.7 % versus 26/
had an assisted birth in France (212/1002, 21.2 % versus 62/214, 28.9 214,12.2 %, p < 0.001) and cesarean (46/342, 13.5 % versus 55/270,
%) or cesarean (342/1344, 25.5 % versus 270/484, 55.8 %). In the 20.4 %, p = 0.02). We do not report any significant differences in terms
Netherlands, more women had a history of PPH regardless mode of birth of maternal mortality (Table 2). The profile of the women who died from
(vaginal birth:144/1002, 25.1 % versus 15/214, 12.9 %, p < 0.001 and severe PPH in both countries is presented in table S5.
for cesarean: 41/342, 17.2 % versus 12/270, 7.8 %, p < 0.001). In
addition, more women in the Netherlands suffered from hypertensive 3.3. Initial PPH-management
disorders than in France after vaginal birth (96/1002, 9.6 % versus 9/
214, 4.2 %, p = 0.01 but not after cesarean birth (39/342, 11.4 % versus We do not report any statistically significant difference in terms of
27/270, 10.1 % respectively, p = 0.58) (Table 1). Main causes of severe initial PPH-management among women with severe PPH between both
PPH were similar among both countries (Table S4). countries. After vaginal birth 677/1002,67.5 % of women with severe
As published in the TeMpOH-1 study, the incidence of severe PPH PPH in the Netherlands received a first-line uterotonics versus 151/
according to our harmonized definition in the Netherlands was 5.0 per 214,71.9 %, p = 0.39 in France and 231/342,67.5 % versus 192/
1000 livebirths (1344/270,101). This is in comparison to the EpiMOMs 270,71.1 % respectively (p = 0.34) after cesarean. See (Table 3).
study in France, which found an incidence of severe PPH of 2.7 per 1,000
livebirths (488/182,309) (Figure S1, Table 1). 3.4. Use and timing of resuscitation and transfusion management

3.2. Adverse maternal outcome Table 2 describes resuscitation/transfusion management per coun­
try. Fibrinogen was given less frequently in the Netherlands than France
Adverse maternal outcome was significantly more prevalent among regardless mode of birth (vaginal birth: 83/1002,8.3 % versus 105/
women with severe PPH in the Netherlands as compared to women with 2014,49.5 %, p < 0.001 respectively; cesarean: 47/342,13.7 % and 152/
severe PPH in France regardless mode of birth (vaginal birth: 793/1002, 270,55.6 %, p < 0.001). Tranexamic acid and rVIIa were significantly
79.1 % and 88/214, 41.1 %, p < 0.001) and cesarean: (259/342, 76.2 % less used after vaginal birth in the Netherlands than France (42.7 %,
versus 160/270, 59.3 % respectively, p < 0.001). Major obstetric 428/1002 versus 55.6 %, 119/214, p < 0.001) and (2.3 %, 23/1002
hemorrhage was more prevalent among women with severe PPH in the versus 6.5 %, p < 0.001) respectively. Time to transfusion after PPH-
Netherlands as compared to women in France both in case of vaginal onset was similar among countries (Table 4).
birth (792/1002,79 % versus 82/214,12.2 %, p < 0.001) and cesarean
(257/342, 75.6 % versus 142/270, 52.6 %, p < 0.001). Peripartum
hysterectomy was significantly less frequently performed in the

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P.L.M. de Vries et al. Preventive Medicine Reports 40 (2024) 102665

Table 2
Univariate analysis. Comparing incidence of adverse maternal outcome in women with severe PPH stratified by mode of birth between France and the Netherlands
(2011–2013).
Vaginal birth Cesarean birth

France The Netherlands France The Netherlands

N = 214 N = 1002 P-value N = 270 N = 342 P-value

n % n % n % n %
Total volume blood loss (L) 1+2 2 (1.6–2.5) 3 (2.5–4.0) <0.001 2 (1.7–3.0) 3 (2.5–4.0) <0.001
Blood loss ≥ 2,5 L 82 (38.3) 792 (79.0) <0.001 142 (52.6) 257 (75.6) <0.001
Hysterectomy 26 (12.2) 27 (2.7) <0.001 55 (20.4) 46 (13.5) 0.02
Maternal death 0 (0.0) 4 (0.4) 0.36 3 (1.1) 3 (0.9) 0.78

Adverse maternal outcome3 88 (41.1) 793 (79.1) <0.001 160 (59.3) 259 (76.2) <0.001
1 2 3
Liters; given with median and interquartile range; composite of hysterectomy, mortality or total volume of blood loss ≥ 2,5L

Table 3
Univariate analysis. Comparing first-line management of PPH in women with severe PPH stratified by mode of birth between France and the Netherlands (2011–2013).
Vaginal Birth Cesarean birth

France The Netherlands P-value France The Netherlands P-value

N = 214 N = 1002 N = 270 N = 342

Manual removal placenta 65 (30.4) 328 (32.8) 0.50 232 (85.9) 301 (88.0) 0.44
Uterine exploration after spontaneous birth placenta 149 (69.6) 658 (65.8) 0.26 30 (11.1) 36 (10.5) 0.81
Urinary catheterization 193 (90.1) 932 (93.0) 0.15 270 (1 0 0) 342 (1 0 0) 1
Oxytocin infusion1 151 (71.9) 677 (67.5) 0.39 192 (71.1) 231 (67.5) 0.34
Time PPH diagnosis – oxytocin infusion (median (IQR)) (minutes) 5 (0–15) 7 (0–18) 0.42 0 (0–5) 1 (0–7) 0.64
1
In France, Oxytocin 5–10 IU slow IV followed by oxytocin infusion of 5–10 IU/h for 2 h (Max: 40 IU). In the Netherlands: Oxytocin 5 IU slow IV, followed by oxytocin
infusion 2.5 IE/4h. PPH = postpartum hemorrhage. IQR = interquartile range

Table 4
Univariate analysis. Comparing transfusion therapy in women with severe PPH stratified by mode of birth between France and the Netherlands (2011–2013).
Vaginal birth Cesarean birth

France N The Netherlands France The

= 214 N = 1002 N= Netherlands
270 N = 342

n (%) n (%) P- n (%) n %) P-

value value

Volume replacement therapy 198 (92.5) 960 (95.8) 0.04 250 (92.5) 303 (88,6) 0.07
Crystalloids 19 (9.1) 95 (9.5) 30 (11.1) 27 (7.8)
Colloids 19 (9.4) 49 (4.9) 4 (1.4) 0 0
Crystalloids and colloids 158 (74.0) 816 (81.4) 216 (80.0) 276 (80,8)
Blood transfusion
Red blood cells 214 (100,0) 1002 (100.0) 1 270 (100.0) 342 (100.0) 1
Number of units1 4 (3–7) 4 (3–5) 5 (3–7) 4 (3–6)
Fresh frozen plasma 196 (92.5) 876 (87.4) 0.04 243 (90.0) 301 (88.9) 0.91
Number of units1 2 (2–4) 2 (2–3) 4 (2–6) 2 (2–5)
Thrombocytes 44 (20.9) 185 (18.5) 0.4 64 (23.7) 110 (32.8) 0.01
Number of units1 1 (1–2) 1 (1–2) 1 (1–3) 1 (1–2)
Hemostatic agents
Fibrinogen 105 (49.5) 83 (8.3) < 150 (55.6) 47 (13.7) <
0.001 0.001
Tranexamic acid 119 (55.6) 428 (42.7) < 140 (52.3) 167 (50.1) 0.51
0.001
Factor VII 14 (6.5) 23 (2.3) < 6 (2.2) 14 (6.5) 0.23
0.001
Time between PPH2 diagnosis and start 95 (48–159) 95 (60–162) 0.94 73 (26–199) 80 (35–130) 0.35
blood transfusion (median (IQR3))
(minutes)
1
among those who were transfused, 2 postpartum hemorrhage, 3
inter quartile range.

3.5. Use and timing of second-line uterotonics 3.6. Use and timing of uterine-sparing interventions

Practitioners in both countries primarily applied sulprostone as After both vaginal and cesarean birth, patients with severe PPH were
second-line uterotonic. These were started significantly later after PPH- significantly (p < 0.001) less likely to be treated with uterine-sparing
onset in the Netherlands than France (vaginal birth: 46 versus 25 min,p interventions in the Netherlands (vaginal birth: 394/1002, 39.3 % and
< 0.001; cesarean: 45 versus 18 min,p < 0.001) (Table 5). cesarean 133/342, 38.9 %) versus France (vaginal birth: 134/214,62.6
% and cesarean 155/270,57.4 %). After vaginal birth, 16/1002, 1.6 % of
women with severe PPH were treated with vascular ligation or

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Table 5
Univariate analysis. Comparing second-line therapy and uterine-sparing interventions in women with severe PPH stratified by mode of birth between France and the
Netherlands (2011–2013).
Vaginal birth Cesarean birth

France The France The Netherlands

Netherlands

N = 214 N = 1002 N = 270 N=

342

Second-line uterotonics N (%) N (%) P- N (%) N (%) P-value

value
Administered 187 (87.3) 826 (82,4) 0.03 192 (71.1) 236 (69.0) 0.35
Ergot alkaloids 0 (0.0) 99 (9,9) 0 (0,0) 28 (8.2)
Sulprostone 178 (83.1) 679 (67,7) 190 (70.3) 221 (64.6)
Misoprostol 9 (4.2) 408 (40,7) 2 (0.7) 83 (24.2)
Time PPH1 diagnosis - second-line uterotonics (median 25 (15–45) 46 (17–90) < 18 (8–45) 45 (12–113) <0.001
(IQR2)) (minutes) 0.001
Uterine sparing interventions
Women with any uterine-sparing intervention 134 (62.6) 394 (39.3) < 155 (57.4) 133 (38.9) <0.001
0.001
Multiple uterine-sparing interventions 28 (13.1) 85 (8.4) 0.03 23 (8.5) 37 (10.8) 0.30
Intra uterine tamponade 86 (40.2) 347 (34.6) 0.12 28 (10.4) 86 (25.2) <0.001
Uterine compression sutures / vascular ligation 30 (14.1) 16 (1.6) < 107 (39.6) 27 (7.9) <0.001
0.001
Embolization 46 (21.5) 116 (11.6) < 43 (15.9) 57 (16.7) 0.89
0.001
1 2
postpartum hemorrhage; inter quartile range.

compression sutures in the Netherlands versus 30/214 (14.1 %) in and stratified by mode of birth in Fig. 1a-1c. In the Netherlands, all types
France (p < 0.001) and 27/342 (7.9 %) against 107/270 (39.6 %) after of uterine-sparing intervention were initiated significantly later in the
cesarean (p < 0.001). Intra-uterine balloon tamponade was more course of refractory PPH (Table 6) In the Netherlands, 101/1121,9%
commonly used in the Netherlands than France after cesarean (86/ women received their first uterine-sparing intervention within the first
342,25.2 % versus 28/270,10.4 %, p < 0.001). Embolization was less hour after onset of refractory PPH versus 253/422,60 % in France (p <
frequently applied in the Netherlands than France after vaginal birth 0.001).
(116/1002, 11.6 % versus 46/214,21.5 %, p < 0.001) but similar in case In total, 41/1121,3.6 % of women in the Netherlands had ≥ 8 L of
of cesarean (Table 5). blood loss versus zero women in France. The profile of these women is
Timing of application of the first uterine-sparing intervention was presented in Table S6.
assessed among 1121 women with refractory PPH (severe PPH re­
fractory to first-line management) in the Netherlands versus 422 women 4. Discussion
in France (Fig. S1) The total volume of blood loss in relation to the time
of onset of the first uterine -paring intervention is displayed for all births We report a higher incidence of adverse maternal outcome among

Fig. 1. a-1c. Forest plot of total blood loss according to time of the first uterine-sparing intervention among women with refractory PPH in France and the
Netherlands between 2011 and 2013 (a) regardless mode of birth (b) for vaginal birth (c) for cesarean birth.

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Table 6
Comparing median timing between onset of refractory PPH and application of uterine sparing-interventions among women with refractory PPH stratified by mode of
birth between France and the Netherlands (2011–2013).
Vaginal birth Cesarean birth

France The Netherlands P-value France The Netherlands P-value

N = 188 N = 868 N = 234 N = 253

Median IQR1 Median IQR Medan IQR Median IQR

2 3
Time between diagnosis refractory PPH - intra-uterine 39 28–115 59 55–220 0.02 45 30–150 95 (54–315) <
tamponade 0.001
Time between diagnosis refractory PPH - compression 107 80–312 291 250–453 < 0.001 36 28–100 250 220–480 <
sutures / ligation 0.001
Time between diagnosis refractory PPH - embolization 127 113–322 206 180–387 < 0.001 152 115–380 270 199–485 <
0.001
1 2
= inter quartile range, = time in minutes, 3 = postpartum hemorrhage.

women with severe PPH in the Netherlands as compared to France. differences in terms of fibrinogen use can explain the increased blood
Although there was no difference between countries in terms of the loss among women in the Netherlands and emphasize the need for more
number of women with severe PPH receiving second-line uterotonics, prospective and randomized trials to define optimal transfusion strate­
we report a statistically significant longer delay before administration of gies among obstetric patients (Deleu et al., 2022).
second-line uterotonics in women with severe PPH in the Netherlands as In contrast with previous data from national obstetric surveillance
compared to France. A larger proportion of women in France received systems, which reported a hemorrhage related maternal mortality ratio
hemostatic agents such as Fibrinogen. After both vaginal and cesarean double as high for France as the Netherlands (0.9 (95 % CI 0.5–1.3)
birth, patients with severe PPH in France were significantly more likely versus 0.4 per 100,000 livebirths (95 % CI 0.0–1.0)), we did not find any
to be treated with uterine-sparing interventions which were applied in significant difference in terms of hemorrhage related maternal mortality
an earlier stage of hemorrhage in France than the Netherlands. in this study (Diguisto and Saucedo, 2022; Ducloy-Bouthors et al.,
The increased risk of adverse maternal outcome among women 2021). This finding could perhaps be explained in two directions: the
suffering severe PPH in the Netherlands as compared to France reported fact that the Epimoms study was not nationwide, or by an under­
in this study, seems mainly due to the fact that more women suffered reporting of maternal deaths in the Dutch national obstetric surveillance
major obstetric blood loss in the Netherlands which is confirmed by the system due to the absence of crosslinking, which has previously resulted
increased volumes of total blood loss among women in the Netherlands. in underestimation of maternal deaths in the Netherlands (Ramler et al.,
This could perhaps be explained by a more expectant management in 2022; Kallianidis et al., 2018).
this country once initial management of PPH has failed, such as The aforementioned findings could be interpreted as a reason to
increased delay before administration of second-line uterotonics and escalate management sooner rather than late. Also, among the maternal
uterine-sparing interventions (NVOG, 2018; Sentilhes et al., 2016). The deaths reported in this study we reported marginal use of uterine sparing
consequences of such delay have also been demonstrated in a large interventions. In line with other data, in the Netherlands 4 out of 7
Canadian cohort of vaginal deliveries, reporting a higher odds for hy­ women died with the uterus still preserved, stressing the importance of
potension and transfusion for every 5-minute additional delay in the timely escalation of management. Nevertheless, our study findings also
administration of a second-line uterotonic (Knoll et al., 2022). The more stress to remain vigilant to the overuse of uterine sparing interventions.
frequent use of intra-uterine balloon tamponade and the low use of Indeed, 40 % of the French women not meeting our inclusion criteria
compression sutures and vascular ligation after cesarean in the were treated by a uterine-sparing intervention which was initiated
Netherlands may also have contributed to the differences in adverse almost simultaneously with second-line uterotonics. In line with the
maternal outcome since intra-uterine balloon tamponade may take a high hysterectomy rate reported in this study in France, this may suggest
longer time to stop the bleeding (Liu et al., 2021; Revert et al., 2017; that obstetricians in France escalate very rapidly when it comes to PPH-
Kong and To, 2018). Reported variations cannot be explained by management, exposing women to the downsides of such escalation.
different recommendations since both countries recommend surgical Earlier studies reported a 9-fold increased risk for hysterectomy among
uterine-sparing interventions as a first step after failure of second-line women who gave birth by cesarean yet by stratifying our analyses to
uterotonics in case of cesarean. This stresses the need to investigate mode of birth we were able to bring to light that the reported differences
whether Dutch recommendations are interpreted differently or whether in terms of hysterectomy between both countries cannot be explained by
obstetricians in the Netherlands feel less inclined to perform hemostatic the fact that more women in France gave birth by cesarean (Kallianidis
surgery and if so, why. In this context, surgical simulation trainings et al., 2020).
could be of interest (Kerbage et al., 2016). The implementation of spe­ The reported incidences of severe PPH in France and the Netherlands
cific PPH-care bundles as recommended by the World Health Organi­ in this study are difficult to compare with other high-income countries
zation could improve guideline adherence (WHO, 2023). Another given the heterogeneity of the applied definitions of severe PPH among
explanation of the reported variations in terms of blood loss could be studies, which are compounded by the lack of a uniform and global
different methods of blood loss quantification applied in both studies. definition of severe PPH (Prick et al., 2015; Kramer et al., 2013; Pet­
However, studies comparing the methods applied in both cohorts do not tersen et al., 2023; Borovac-Pinheiro et al., 2018). Perhaps these dif­
report any evidence to consider one method as more accurate over the ferences could be explained by the reported variations in terms of mode
other method (Diaz et al., 2018). of birth or by differences in PPH risk-factors such as hypertensive dis­
We report a higher use of hemostatic agents among women with orders and history of PPH. The higher proportion of women with vaginal
severe PPH in France. It has been hypothesized that hypofibrinogemia is birth in the Netherlands may have resulted in increased barriers and
a marker of the risk of severe PPH suggesting early supplementation delays before escalation to more invasive management. This may also be
could reduce severity of PPH (Cortet et al., 2012). However, this hy­ compounded by several elements pertaining to maternity care in this
pothesis was not confirmed by recent studies, showing no reduction of country. First, the culture in the Netherlands might revolve more around
blood loss or improved maternal outcomes after early and systematic the notion that physiological birth should proceed without unnecessary
treatment with fibrinogen. These findings make it unlikely that the interventions, a notion strongly present among parturients and

6
P.L.M. de Vries et al. Preventive Medicine Reports 40 (2024) 102665

practitioners (Johnson et al., 2007). Second, differences in clinical the finding that patients in France were more likely to have an operative
practices with regards to manual removal of the placenta between or cesarean delivery than those in the Netherlands, allowing for more
France and the Netherlands may contribute to the delay in the expeditious access to uterine sparing interventions and hysterectomy.
Netherlands before proceeding to more invasive interventions. In the
Netherlands, women are generally transferred to the operating theatre CRediT authorship contribution statement
for general anesthesia for manual removal of the placenta whereas in
France this is performed at the labor ward with the epidural that was P.L.M. de Vries: Conceptualization, Data curation, Formal analysis,
already in place for labor (Seijmonsbergen-Schermers et al. (2018), Investigation, Methodology, Validation, Visualization, Writing – orig­
Cheung et al. (2011)). The reported differences in terms of mode of inal draft. C. Deneux-Tharaux: Writing – review & editing, Validation,
delivery among women with severe PPH in both countries cannot be Supervision, Methodology, Conceptualization. C. Caram: Writing – re­
explained by differences in general cesarean section rates alone which view & editing, Visualization, Validation, Methodology, Formal anal­
were 16.6 % in the Netherlands versus 20.2 % in France during the ysis, Data curation. F. Goffinet: Writing – review & editing, Validation,
study-period (Kerbage et al., 2016; WHO, 2023). They may reflect var­ Methodology, Conceptualization. D.D.C.A. Henriquez: Data curation,
iations between specific targets in PPH management resulting in Validation, Writing – review & editing. A. Seco: Visualization, Valida­
increased risk of severe PPH after cesarean in France such as suboptimal tion, Methodology, Data curation. J.G. van der Bom: Writing – review
postoperative surveillance, as has been suggested by earlier reports from & editing, Validation, Methodology, Conceptualization. T. van den
the French national confidential enquiry, or by an increased risk of PPH Akker: Conceptualization, Writing – review & editing, Supervision,
among women given birth vaginally in the Netherlands due to the spe­ Validation, Methodology.
cific elements pertaining to maternity care in the Netherlands specified
above. Declaration of competing interest
The increased number of women with hypertensive disorders and
history of PPH in the Netherlands may warrant a more proactive The authors declare that they have no known competing financial
approach of these women, as has been highlighted by earlier studies interests or personal relationships that could have appeared to influence
(Schaap et al., 2019; Zwart et al., 2008). Another explanation could be the work reported in this paper.
differences in initial management of hemorrhage, leading to more
women with severe PPH in the Netherlands. This seems however to be Data availability
an unlikable explanatory mechanism as we did not report any differ­
ences in terms of prophylactic and initial management of hemorrhage. Data will be made available on request.
This study is one of few comparing extensive data on timing of PPH
management and maternal outcome in women with equally severe PPH Acknowledgements
from two countries with comparable resources. Both countries provided
detailed information on the timing of interventions, an important For the Epimoms data: The authors thank the coordinators of the
determinant of PPH-related maternal outcome. Setting up a randomized participating regional perinatal networks (Alsace, Aurore, Auvergne,
controlled trial to test the efficacy of a therapeutic sequence in the Basse-Normandie, MYPA, NEF, Paris Nord, 92 nord, Lorraine) for their
treatment of refractory PPH is very challenging; in this context, inter­ help in the coordination of women’s inclusion and data collection in
national comparisons between countries with different management their region; Chloé BARASINSKI, Sophie BEDEL, Aline CLIN D’AMOUR,
strategies offer a valuable quasi-experimental alternative for generating Laurent GAUCHER, Isabelle LECREFF, Blandine MASSON, Carole
evidence. Although the EpiMOMs cohort was not nationwide, the large RAMOUSSET, Mathias ROSSIGNOL, Zelda STEWART, Dalila
source population had characteristics similar to the national profile. TALAOURAR, Yacine TOURE, and Nicole WIRTH for their contribution
Both databases were collected over comparable time-periods, reducing to the implementation of the EPIMOMS study in their regions; the ob­
the probability that differences in outcome are the result of temporal stetricians, midwives, and anesthesiologists who contributed to case
trends in maternal characteristics. Main limitations arise from the fact identification and documentation in their hospitals; the research assis­
that clinical practices may have changed since data from both the co­ tants who collected the data and Coralie Chiesa-Dubruille for the na­
horts were collected. However, guidelines from both countries did not tional supervision of study implementation. For the Tempoh data: We
have any major revisions during the study-period besides from the use of would like to thank all 61 participating hospitals and the Dutch Con­
intra-uterine balloon tamponade as a bridging step after vaginal birth in sortium for Healthcare Evaluation and Research in Obstetrics and
the 2014 revision of the French guideline. Although this could have Gynaecology – NVOG Consortium 2.0, medical students R.M. Loeff, R.J.
resulted in an underuse of intra-uterine balloon tamponade in France in van Goeverden, B. Eijlers, A.Hillebrand, S.E. Spelmink, T.J. Beunder, V.
our study as compared to current practices, we consider the imple­ Harskamp, M. Wind, M.D. Koning, R.A. Cramer, A. Veenstra, S.M. Smith
mentation of guidelines as a continuous process making it likely that this and E.E. Ensing, datamanagers C.J. van Brussel-de Groot and O. Zouitni,
tool was already current practice among practitioners in 2012–2013. and research nurses C. Kolster-Bijdevaate, M.S. Bourgonje-Verhart, C.E.
From the French source population, we excluded 79 women due to Bleeker-Taborh and E. Roos-van Milligen for their contributions to the
missing data on the total quantity of blood loss or blood transfusion. data collection for the TeMpOH-1 study.
From these women, 24 had an invasive intervention to treat PPH and the
fact that these women could not be included in our analyses could
Appendix A. Supplementary data
potentially have induced a selection bias.
Supplementary data to this article can be found online at https://doi.
5. Conclusions org/10.1016/j.pmedr.2024.102665.

We report a higher incidence of adverse maternal outcome among

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