Potential Predictive Factors for Postpartum …1299486/FULLTEXT01.pdf4 Abstract Objective. To...
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WRITTEN REPORT Medicine programme, degree project (30.0 c)
Potential Predictive Factors for Postpartum Endometritis and the
Microbiology in Cervical Cultures.
Written by: Ellinor Eriksson
Supervisor: Maria Jonsson
Date: 2018-08-27
Uppsala University
Department of Women’s and Children’s Health
2
Potential predictive factors for postpartum endometritis and the microbiology in
cervical cultures. Written by: Ellinor Eriksson
Illustration on front page: Ellinor Eriksson, 2018.
Table of contents Populärvetenskaplig sammanfattning (Summary in Swedish) ................................................... 3
Abstract ...................................................................................................................................... 4
List of abbreviations ................................................................................................................... 5
Definitions .................................................................................................................................. 5
Background ................................................................................................................................ 6
Description of the condition ................................................................................................................ 6
Pathogenesis and microbiology ........................................................................................................... 7
Prognosis ............................................................................................................................................. 7
Prevention ............................................................................................................................................ 8
Treatment ............................................................................................................................................ 9
Risk factors .......................................................................................................................................... 9
Importance of this study .................................................................................................................... 10
Objectives .......................................................................................................................................... 10
Material and methods ............................................................................................................... 11
Study design and settings .................................................................................................................. 11
Study population................................................................................................................................ 11
Data collection ................................................................................................................................... 11
Ethical approval ................................................................................................................................. 11
Variables ............................................................................................................................................ 12
Statistical analysis ............................................................................................................................. 12
Results ...................................................................................................................................... 14
Discussion ................................................................................................................................ 18
Potential predictive factors ................................................................................................................ 18
Microorganisms in cervical cultures ................................................................................................. 20
Strengths and limitations ................................................................................................................... 21
Conclusion ......................................................................................................................................... 23
Acknowledgement ............................................................................................................................. 23
References ................................................................................................................................ 24
Appendix 1 – List of variables ................................................................................................. 31
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Populärvetenskaplig sammanfattning (Summary in Swedish) Postpartumendometritit (PPE) är en infektion i livmoderslemhinnan som drabbar ungefär 1 av
50 kvinnor efter förlossning. Diagnosen ställs vanligen vid feber i frånvaro av annan
infektionsorsak. Nedre buksmärta, illaluktande flytningar och förhöjda infektionsprover är
kliniska fynd som stärker misstanken, men vilka inte är specifika för PPE. Infektionen är
vanligtvis lindrig men de flesta patienter kräver antibiotikabehandling. Med adekvat
behandling är prognosen god men komplikationer kan tillstöta såsom abscesser, sepsis,
septiska embolier, toxiskt chocksyndrom och i värsta fall död. Globalt är infektion den tredje
största orsaken till mödradödlighet, motsvarande drygt tio procent. Trots att PPE är en relativt
vanlig och i vissa fall allvarlig diagnos är det fortfarande inte helt känt vilka bakterier som
orsakar infektionen.
Det finns flera föreslagna riskfaktorer för PPE. Kejsarsnitt är den viktigaste och mest
studerade. Antibiotikaprofylax rekommenderas till kvinnor förlösta med kejsarsnitt, vid
intrapartal feber samt på vissa kliniker vid långvarig vattenavgång (LVA), trots att evidensen
för antibiotikaprofylax vid LVA är omdiskuterat. Det finns fler faktorer som är associerade
till PPE men där evidensen är lägre och studieresultaten skiljer sig.
Vår studie visar att manuell lösning av moderkakan är oberoende associerat till PPE vid
vaginal förlossning. Andra faktorer som tycks vara associerade, men som kan vara beroende
av varandra, är överburenhet, igångsättning av förlossning, värkstimulerande behandling,
förlängt utdrivningsskede och kejsarsnitt trots antibiotikabehandling. Det är en liten studie
och mer forskning behövs för att bättre kunna identifiera riskfaktorer. Nyttan med
antibiotikaprofylax till riskgrupper vid vaginal förlossning bör även studeras i randomiserade
kontrollerade studier.
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Abstract Objective. To evaluate predictive factors for postpartum endometritis and to describe the
microbiology. Design. Case-control study. Setting. Uppsala University hospital, Sweden in
2017. Methods. Cases (n =57) were women who had a vaginal onset of labour and who,
within 14 days postpartum, were diagnosed with endometritis. Controls (n = 114) were the
first two women giving birth after each case, matched for parity. Multiple gestation, elective
caesareans, preterm births (<34 weeks) and intrapartum fever (≥38.0°C) were excluded. Data
were collected from medical records, partograms and results of the cervical cultures. Crude
and adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic
regression. Results. Post-term delivery (≥42 weeks), induction of labour, prolonged duration
of second stage, oxytocin treatment, caesarean section and manual placental removal were
associated with postpartum endometritis. Only manual placental removal (OR 11.3, 95% CI
1.2-102.4) persisted in the multivariate analysis. Cervical cultures were obtained from the
majority of the cases but only 47.1% were positive and showed diversity. Conclusion. Manual
placental removal is a predictive factor for postpartum endometritis. Other potential predictive
factors found in this material need to be evaluated in larger studies. The microbiology of the
infection is still not clearly defined.
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List of abbreviations
American College of Obstetricians and Gynecologists – ACOG
Body Mass Index – BMI
Confidence interval – CI
Interquartile range – IQR
Meconium-stained amniotic fluid – MSAF
Odds ratio – OR
Postpartum endometritis – PPE
Prolonged rupture of membrane – PROM
Toxic shock syndrome – TSS
World Health Organization – WHO
Microorganisms
Escherichia coli – E coli
Gardnerella vaginalis – G vaginalis
Group A streptococcus – GAS
Group B streptococcus – GBS
Group G streptococcus – GGS
Staphylococcus aureus – S aureus
Definitions See appendix 1 for list of definitions.
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Background
Description of the condition
The diagnosis of postpartum endometritis (PPE) is clinical, and mainly based upon the
presence of postpartum fever in absence of any other infectious aetiology. The American
Committee on Maternal Welfare defines puerperal febrile morbidity as an “oral temperature
of 38.0℃ or higher on any two of the first ten days postpartum”, excluding the first 24 hours.1
Low grade fever during the first day is not uncommon and often passes spontaneously, and is
therefore excluded in the definition.2 Midline abdominal pain, purulent or foul-smelling
lochia, uterine tenderness and leucocytosis are common clinical findings supporting the
diagnosis of endometritis but are variable and nonspecific for the condition.3 Abrupt
occurrence of fever exceeding 38.9°C and severe abdominal pain is more often associated
with PPE caused by group A streptococcus (GAS). However, it is not possible to clinically
determine the aetiology of the infection4. Symptoms can manifest hours to several days after
childbirth – contributing to difficulties in identifying cases – especially after hospital
discharge.5 Failure to identify signs of infection delays the diagnosis and treatment which
increases the risk of morbidity and mortality.6
PPE is diagnosed after 0.2% to 3.6% of vaginal deliveries and it is up to 21 times more
common after caesarean deliveries.7,8 The incidence of PPE in Sweden in 2015 was 1.9%
after vaginal births and 3.6% after caesarean deliveries including both elective and emergency
caesareans. The total incidence of PPE in Sweden was between 1.3% to 3.6% altogether.9 In a
cross-sectional study from a hospital in Denmark, investigating women giving birth during
May 2007 to April 2008, the incidences within four weeks postpartum were 2.0% after
vaginal delivery, 2.0% after elective caesarean delivery and 5.0% after emergency caesarean
delivery. The total rate after all deliveries was 2.0%.10 In 1995 to 2000 at a hospital in the
United States, 1.6% of all women giving birth were diagnosed with PPE. The rate was 0.5%
among women with vaginal delivery and 7.0% among women with caesarean delivery, both
elective and emergency caeasareans.11 In a trial from Israel from 2000, the rates were 0.2%
after vaginal delivery and 2.6% after caesarean delivery.7 A study in Uganda presented a total
incidence of PPE of 1.8%, of which 86% had had caesarean deliveries.12
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Pathogenesis and microbiology
PPE is an infection of the decidua, the part of the endometrium that changes before and during
pregnancy. The infection often occurs during labour and delivery due to contamination of the
uterine cavity and invasion of the endometrium by cervicovaginal organisms.3 The occurrence
of infection depends on the interaction among the quantity of bacterial inoculum, the
virulence of the present bacteria and the host’s mechanisms of defeating infection.13
The microbiological aetiology is rather difficult to identify and is not clearly defined. Unless
blood cultures are positive or the genital culture is obtained from the upper genital tract
without contamination from the vagina, the infection is rarely laboratory confirmed.3 The
typical infection is polymicrobial and more than one organism is usually found in the cultures,
often a mixed aerobic and anaerobic flora.14
There are many different microorganisms associated to PPE, suggested as potential
pathogens. The largest bacterial groups are Ureaplasma urealyticum, Mykoplasma hominis,
organisms associated with bacterial vaginosis, such as Gardnerella Vaginalis (G vaginalis),
Bacteroides species, Peptostreptococcus species and Bacteroides bivius15, and other
miscellaneous facultative and anaerobic bacteria, including Escherichia coli (E coli) and
Streptococci.14 Streptococci is the most common gram-positive facultative microorganism
including for example group B streptococcus (GBS), enterococci, such as Enterococcus
faecalis, and other streptococci. In some patients Staphylococcus aureus (S aureus) can be
found in the endometrial cultures without any other pathogen present.14 Some suggests
Streptococcus agalactiae, a type of GBS, as the primary pathogen implicated.16 PPE caused
by GAS are rare, however, endometritis is a common presentation of GAS infection in the
puerperium.4 In addition to those bacteria mentioned, Peptococcus species and Clostridium
species are possible microorganisms, causing particularly post-caesarean endometritis.17
Prognosis
Nowadays, most cases of PPE are rather mild and cured by proper administration of antibiotic
therapy. However, puerperal fever has been a common cause of maternal mortality before the
antibiotic era, and is still a common cause for complications in low-income countries if
treated inadequately. Globally, infection is the third largest direct reason to maternal
mortality, corresponding for just over ten percent.18 Since the use of antibiotics has increased,
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a sharp decrease in maternal morbidity of PPE has been observed. Therefore, antibiotic
therapy is generally accepted as the golden standard of treating PPE. Even though the
prognosis of PPE is generally good there are complications of the condition. These includes
formation of intra-abdominal and pelvic abscesses, extension of the infection to peritoneal
cavity triggering peritonitis, sepsis, septic pelvic thrombophlebitis that might cause septic
pulmonary embolism and even death.3 In presence of toxin-producing GAS, necrosis of tissue
and local clotting of blood vessels are possible even after administration of antibiotics. The
produced toxins do not respond to antibiotic treatment and can continue to leak into the
vasculature, producing a widespread organ failure and toxic shock syndrome (TSS). If TSS
derives after antibiotic treatment, it is evidence of the infection being aggressive and
untreatable by antibiotics and that the release of toxins will be large enough to cause septic
shock. In such cases, prompt surgery and hysterectomy are required to stop organ damage and
to reverse spreading of infection.4
Prevention
The basis of preventing infection in women undergoing uncomplicated vaginal births is basic
hygiene and infection control measures such as hand washing and disinfection, proper use of
disposable gloves, minimizing vaginal examinations and sterilization of equipment.5,19 In
addition, prophylactic antibiotics is now routine in the prevention of PPE in elective and
emergency caesarean deliveries and in the event of intrapartum fever (temperature of 38.0°C
or higher).20–23 In some clinics antibiotic prophylaxis is recommended in case of prolonged
rupture of membranes (PROM, i.e. longer than 18 hours prior to childbirth)24. However, there
are no convincing evidence of benefits in either maternal or neonatal risk of infection from
use of routine antibiotics for PROM (longer than 16-24 hours) near or at term.25
Administration of intrapartum prophylactic antibiotics is also routinely given to women
colonized with GBS or at preterm labour (less than 37 gestational weeks) although mainly to
prevent neonatal infection.26,27
The significance of prophylactic antibiotic treatment after uncomplicated vaginal births has
been studied, and the results indicate that routinely antibiotics – administrated intrapartum or
within 1 hour after delivery – reduces the incidence of PPE by up to 70%. However, the
studies are few and of rather low quality which limits the interpretation of evidence.28 The
usage is therefore not recommended or praxis in Sweden. Furthermore, the incidence of PPE
is rather low which indicates that a large number of women need to be treated in order to
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avoid a small number of cases.28 The risks of antibiotic-related side effects and the emerging
antibiotic resistance also need to be considered.29
Treatment
Choice of treatment of PPE depends on timing and clinical severity. Women with mild
endometritis in a good general condition can usually be treated outside of the hospital using
broad-spectrum oral antibiotics – such as amoxicillin/clavulanic acid, possibly with addition
of metronidazole.30,31 For treating severe PPE, there are a few different empiric antibiotic
regimens. The most effective treatment is the combination of intravenous clindamycin and
once-daily dosing of gentamicin which has a small number of treatment failures and wound
infections. Successful treatment is usually defined as absence of fever for 24 to 48 hours.3
Risk factors
Several factors may contribute to the risk of developing PPE, both pre-existing maternal
conditions and complications that may occur during labour and childbirth. The most important
risk factor for developing PPE is caesarean section, especially when performed after vaginal
onset of labour. The procedure increases the risk 6 to 21 times compared to the risk at vaginal
delivery.7,11 Operative vaginal delivery (forceps and vacuum delivery) is suggested a risk
factor as well.13
Maternal age less than 17 years32 and presence of certain genital tract bacteria are pre-labour
characteristics associated with PPE. Bacterial vaginosis during pregnancy increases the total
risk of PPE two to three times compared with women without bacterial vaginosis.33,34 At
caesarean delivery, studies have shown an up to sixfold increased risk.35
The association to time-related events during delivery has been studied extensively and some
events are suggested as risk factors for PPE. In one study, five time-related peripartum events
were investigated including duration of labour, duration of ruptured membranes, the number
of vaginal examinations, the time from first vaginal examination to delivery and duration of
internal monitoring. The results from that study indicate that duration of labour is the primary
determinant of postpartum morbidity and suggest that other time-related events may only be
associated to an increased risk of PPE due to correlation to a prolonged duration of labour.36
Other more recent studies imply that PROM (longer than 16-24 hours) significantly increases
the risk for PPE isolated from duration of labour.13,32,37 There are more studies to support that
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prolonged labours is a risk factor38, whereas other studies33,39 found no increased risk of PPE.
Despite the possible association between endometritis postpartum and long labours, there are
no randomized controlled studies investigating possible benefits of prophylactic antibiotics or
guidelines of its usage.
There are more intrapartum variables associated to PPE such as gestational age. Beyond 40
gestational weeks, the risk of PPE increases with every week up to 42 weeks.40 Gestational
age of less than 37 weeks has also been shown to increase the risk for PPE.7 In the event of
meconium-stained amniotic fluid (MSAF), the risk of developing clinical PPE is doubled.41
There are studies investigating the benefits of prophylactic antibiotics at MSAF showing no
statistically significant reduction in incidence of PPE.41 Other – not uncommon –
complications to delivery, increasing the risk of PPE, are manual removal of placenta after
vaginal delivery and postpartum anaemia after both vaginal and caesarean delivery.32,42,43 The
incidence of retained placenta, which is the leading cause to manual removal, is 0.1% to 3%.
It is less common in developing countries, however with a high fatality rate of up to 10%.44,45
There are no randomized controlled trials comparing antibiotic prophylaxis and non-antibiotic
use or placebo to prevent PPE after manual removal of placenta at vaginal birth46 but a
systematic review of non-randomized studies showed no significant reduction in incidence.47
Importance of this study
PPE contributes considerable to maternal morbidity and mortality and there might be an
opportunity for prevention. Antibiotics are suggested prophylaxis but the evidence of profit of
routinely administration of antibiotics to all women after uncomplicated vaginal birth is low.
However, antibiotics are used as prophylaxis to prevent endometritis in some events such as
caesarean section and intrapartum fever. It might also be beneficial in other specific situations
that evolve during labour, also in women with vaginal delivery, such as manual removal of
placenta and delayed long labours. To choose antibiotic treatment or prophylaxis, knowledge
of microorganisms causing infection, is crucial.
Objectives In a Swedish setting, we aimed to identify clinical variables associated to postpartum
endometritis in women with vaginal onset of labour and, to describe the microbiology of the
condition.
11
Material and methods
Study design and settings
This is a case-control study from the Department of Obstetrics and Gynaecology at Uppsala
University Hospital in Sweden, which is a referral centre with approximately 4000 deliveries
yearly. The period studied was January 1st to December 31st 2017. The study also includes a
descriptive analysis of microorganisms present in cervical cultures of the cases.
Study population
Cases were women who had a vaginal onset of labour who within 14 days postpartum were
diagnosed with postpartum endometritis according to the medical records (ICD-10 code
O85.9). Since there are no universally accepted criteria for the condition, the outcome was
based on the clinical diagnosis by the physician. Exclusion criteria included elective caesarean
sections, preterm gestational age (less than 34 weeks), multiple gestation and, fever
(temperature of 38.0°C or higher) at arrival to the delivery ward. The first two women
registered at the delivery unit after each study case were chosen as controls and matched for
parity. The same exclusion criteria as for the cases applied for the controls.
Data collection
Data were collected from medical records during January to March 2018. A database
containing data of diagnoses entered from the healthcare information system Cambio
COSMIC was searched for women diagnosed with postpartum endometritis during the set
period of time. Controls were found in a register of all women in labour organized by order of
arrival to the ward, maintained by the delivery unit at Uppsala University Hospital. Medical
records, including partograms, were reviewed and data of chosen variables were retrieved. To
isolate potentially pathogenic microorganisms, cervical cultures were taken from most of the
cases at the time of return to the hospital. Urine cultures were also taken from most of the
patients, but those results were of no importance in this study. Endometrial cultures were not
taken from any of the women why results of the cervical cultures were the chosen method to
identify microorganisms. The results from the cultures were reviewed to find present
microorganisms.
Ethical approval
No application to the Research Ethics Committee was needed since this study is a quality
control of the medical care conducted at Uppsala University Hospital and contributes to
12
development of the care. However, permission to review medical records of patients was
given by Masoumeh Isfahani Rezapour, Operational manager of the Department of Women´s
health and Sune Larsson, Director of research and education at Uppsala University Hospital.
There was no interaction with any of the subjects.
Variables
Information on parity, age, Body Mass Index (BMI), infertility treatment, tobacco use,
intercurrent diseases, pregnancy complications, gestational age, duration of rupture of
membrane, induction of labour, colour of amniotic fluid, duration of different stages of
labour, oxytocin treatment, epidural anaesthesia, number of vaginal examinations, attendance
of student, mode of delivery, foetal presentation, foetal birth weight, maternal blood loss,
maternal blood transfusion, manual removal of placenta and uterine atony. A list of variables
with definitions and methods of collection and calculation can be found in Appendix I.
Statistical analysis
IBM SPSS Statistics Subscription 2017 for Windows was used to perform statistical analysis.
Chi Square test or Fisher’s exact test were applied to compare distribution of categorical
variables between groups. Fisher’s exact test was chosen when the number of values in any
group were smaller than four. For continuous variables, Mann-Whitney U test was applied
when data were non-parametric and T-test when data were parametric. P-value <0.05 was
considered statistically significant. Logistic regression was used to calculate odds ratio (OR)
with 95% confidence interval (CI).
Multivariate logistic regression was used to identify independent predictors since some of the
variables are interrelated. Variables entered in the multivariate analysis were post-term
pregnancy (42 weeks or later), induction of labour, second stage of 3 hours or longer,
caesarean section and manual removal of placenta. Second stage of 3 hours or longer were
used instead of the continuous variable of duration of second stage since a cut-off value is of
more clinically use. 3 hours were the cut-off value with the lowest p-value (p 0.06) and
therefore used in the multiple regression. Women who did not reach second stage because of
caesarean section were not considered in the variable second stage of 3 hours or longer. The
same applied to women delivering by caesarean section in the variable manual removal of
placenta. The variable oxytocin treatment was excluded from the multivariate analysis since
13
most of the women who were induced got oxytocin treatment, why both variables were not
included. OR with 95% CI was calculated.
14
Results
During the study period there were 4,169 births (3,477 vaginal births (83.4%), 374 emergency
caesareans (9.0%) and 318 elective caesareans (7.6%)) at Uppsala University Hospital. Out of
these, 65 women (1.6%) were diagnosed with postpartum endometritis in total, of which 56
women delivered vaginally, 8 women by emergency caesarean and 1 woman by elective
caesarean. The incidences of PPE were 1.6% after vaginal delivery, 2.1% after emergency
caesarean and 0.3% after elective caesarean (1.3% after all caesarean deliveries in total). 57
women met our inclusion criteria and formed the case group (Figure 1).
Figure 1. Flowchart of cases.
Table 1 describes maternal characteristics. There were no significant differences between the
groups in terms of age, BMI and tobacco use. The total number of women with intercurrent
diseases did not differ. However, psychiatric diagnoses were more common among cases,
22.8% vs 10.5% (p 0.03). Pregnancy complications did not differ between groups in total but
fewer cases suffered from premature contractions, 15.8% vs. 30.1% (p 0.04).
Total number of deliveries at
Uppsala University hospital 2017
N = 4169
Study population
n = 57
PPE diagnosed >14 days
postpartum
n = 7
Elective caesarean section
n = 1
Women not diagnosed with PPE
n =4104
15
Table 1. Maternal characteristics in the case and control groups.
Characteristics
Cases
n = 57
Controls
n = 114
p-value
First vaginal delivery
previous caesarean delivery
35 (61.4)
5 (8.8)
66 (57.9)
5 (4.4)
0.66
0.25
Age (years) 30.3 ± 6.1 30.0 ± 4.9 0.75
BMI (kg/m2) 24.2 (21.9-27.7) 23.8 (21.5-26.6) 0.74
Infertility treatment 7 (12.3) 6 (5.3) 0.11
Tobacco use
missing
11 (19.3)
1
15 (13.8)
5
0.35
Intercurrent diseases
Diabetes mellitus
Hypertensive disorders
17 (29.8)
0 (0.0)
7 (12.3)
31 (27.2)
5 (4.4)
9 (8.0)
0.72
0.17*
0.36
Pregnancy complications
Colonization of Group B Streptococcus
48 (84.2)
1 (1.8)
102 (90.3)
9 (8.0)
0.25
0.17*
Values are given a n (%), means ± standard deviation (SD) or medians (quartiles).
Bolded = significance. * Fischer’s exact test.
BMI = Body Mass Index
IVF = In vitro fertilisation
In Table 2 variables related to labour are displayed. Using univariate analyses, six clinical
variables related to labour were found associated with PPE. Post-term delivery (42 weeks or
later) was significantly more common among cases (15.8%) than controls (5.3%) but the
mean gestational age did not differ between groups. There was a higher rate of induction of
labour among cases (36.8% vs. 21.9%) and prostaglandins were used more often. We found
no difference in duration from start of induction to delivery. Duration of second stage was
significantly longer (p 0.03) in the case group. The median duration of second stage was 97
minutes (interquartile range (IQR) 37-184 minutes) among cases and 48 minutes (IQR 16-153
minutes) among controls. There were no differences regarding total duration of labour,
duration of first stage or duration of bearing down effort. The use of oxytocin infusion was
more frequent among cases (71.9% vs. 53.5%) but we found no difference regarding
diagnosis of uterine inertia. There were no differences in rates of amniotomy, epidural use,
prolonged rupture of membranes or number of vaginal examinations performed, even after
correction for examinations performed by students. Cases more often delivered by caesarean
section (14.0% vs. 5.3%). The median amount of blood loss was 400 ml (300-800 ml) among
cases and 300 ml (250-456 ml) among controls (p 0.06). There was no significant difference
between blood loss of 1000 ml or above, which is the limit used for postpartum haemorrhage.
Manual removal of placenta was needed among 5 cases (8.8%) compared to 1 control (0.9%)
(p 0.02). Controls had longer hospital stay, 2 days (IQR 1-3 days) vs. 1 day (IQR 1-2 days),
after delivery (p 0.02).
16
Table 2. Clinical variables related to labour in the case and control groups.
Characteristics
Cases
n = 57
Controls
n = 114
p-value
Gestational age (weeks)
Post-term delivery (≥42 weeks)
39.6 ± 1.7
9 (15.8)
39.7 ± 1.3
6 (5.3)
0.69
0.02
Prolonged rupture of membrane (≥24 h) 11 (19.3) 13 (11.4) 0.16
Induction of labour 21 (36.8) 25 (21.9) 0.04
Time of induction of labour (min) 937 (511-1520) 708 (300-1624) 1.00
Cervical ripeness at induction
Favourable
Unfavourable
5 (23.8)
16 (76.2)
10 (40.0)
15 (60.0)
0.24
Method of induction of labour
Amniotomy
Oxytocin
Foley catheter
Prostaglandin
Double-balloon catheter
4 (7.0)
1 (1.8)
5 (8.8)
11 (19.3)
0 (0.0)
9 (7.9)
1 (0.9)
3 (2.6)
10 (8.8)
2 (1.8)
1.00
1.00*
0.12*
0.05
0.55*
Meconium-stained amniotic fluid
missing
11 (21.2)
5
13 (11.5)
1
0.10
Total duration of labour (min)
First stage
missing
Second stage
Second stage ≥ 3 hours
Bearing down effort
missing
360 (169-610)
263 (137-438)
4
97 (37-184)
15 (28.3)
23 (11-50)
8
271 (113-559)
217 (110-432)
12
48 (16-153)
17 (15.6)
20 (12-34)
9
0.30
0.46
0.03
0.06
0.17
Oxytocin treatment 41 (71.9) 61 (53.5) 0.02
Uterine inertia
Primary
Secondary
missing
24 (42.1)
9 (15.8)
15 (26.3)
0
39 (34.5)
15 (13.3)
24 (21.2)
1
0.33
0.66
0.46
Epidural anaesthesia 35 (61.4) 53 (46.5) 0.07
Number of vaginal examinations 6 (4-10) 5 (3-9) 0.27
Operative delivery
Vacuum extraction
Caesarean section (vaginal onset)
6 (10.5)
8 (14.0)
9 (7.9)
6 (5.3)
0.57
0.05
Foetal presentation
Vertex, occiput anterior
Vertex, occiput posterior
Breech
51 (89.5)
5 (8.8)
1 (1.8)
105 (92.1)
7 (6.1)
2 (1.8)
Birth weight (g)
missing
3600 (3342-4003)
5
3533 (3214-3836)
6
0.78
Blood loss (ml) 400 (300-800) 300 (250-456) 0.06
Blood loss ≥ 1000 ml 8 (14.0) 8 (7.0) 0.14
Blood transfusion 3 (5.3) 2 (1.8) 0.36*
Manual removal of placenta 5 (8.8) 1 (0.9) 0.02*
Uterine atony 8 (14.0) 8 (7.0) 0.14
Values are given as n (%), means ± standard deviation (SD) or medians (quartiles).
Bolded = significance. * Fischer’s exact test
17
Crude and adjusted ORs (95% CIs) from the multivariable logistic regression are shown in
Table 3. Statistical significance persisted for manual removal of placenta (adjusted OR 11.3
95% CI 1.2-102.4).
Table 3. Crude and adjusted odds ratios for intrapartum variables.
Characteristics
Crude OR (95% CI)
Adjusted OR (95% CI)
Post-term delivery ≥42 weeks 3.4 (1.1-10.0) 3.2 (0.9-11.4)
Induction of labour 2.1 (1.0-4.2) 1.3 (0.6-3.1)
Second stage ≥ 3h 2.1 (1.0-4.7) 2.0 (0.9-4.8)
Caesarean section 2.9 (1.0-8.9) 7.0 (0.7-68.5)
Manual removal of placenta 13.3 (1.6-113.3) 11.3 (1.2-102.4)
OR = odds ratio. CI = confidence interval.
Cervical cultures were obtained from 51 cases (89.5%). In 24 of the cultures (47.1%) one or
more microorganisms were found. Two of the cultures contained two microorganisms each,
one with G vaginalis and S aureus and the other one with group G streptococcus (GGS) and S
aureus. The other 22 cultures – containing microorganisms – obtained only one
microorganism each. Table 4 shows the panorama of microorganisms. The most frequent
microorganism was S aureus, found in 5 cultures (9.8%). The three most frequent
microorganisms after S aureus were GBS, GGS and G vaginalis, found in 4 cultures each.
Two of the cultures were not tested for G vaginalis.
Table 4. Microorganisms of the cervical cultures.
Type of microbe
n (% of cultures taken)
Staphylococcus aureus 5 (9.8)
Group B Streptococcus (Streptococcus agalactiae) 4 (7.8)
Group G Streptococcus 4 (7.8)
Gardnerella vaginalis1 4 (7.8)
Escherichia coli 3 (5.9)
Bacteroides fragilis 3 (5.9)
Group A Streptococcus (Streptococcus pyogenes) 1 (2.0)
Group C Streptococcus 1 (2.0)
Clostridium perfringens 1 (2.0)
Cultures with any microorganism
24 (47.1)
Cultures without microorganisms 27 (52.9)
No cervical culture taken 6 1two isolates were not tested for Gardnerella vaginalis.
18
Discussion
Potential predictive factors
PPE is the most common obstetric infection48, contributing to maternal morbidity and
mortality. The aim of our study was to evaluate potential predictive factors for PPE in women
with vaginal onset of labour. The total rate of PPE was 1.6% in Uppsala in 2017. The
incidences were 1.6% after vaginal deliveries, 2.1% after emergency caesareans and 0.3%
after elective caesareans. The incidences correlate with rates found in the literature but the
difference in rate between vaginal and caesarean delivery is smaller than in other studies.7,11
Whether the small difference between incidences in our study is due to a high incidence of
PPE after vaginal deliveries or if the incidence of post-caesarean endometritis is low in our
study population cannot be known for sure. Compared to the incidences in Uppsala in 2015,
both incidences are lower9. The same goes for a cross-sectional study of 1871 women in
Denmark from 2007 to 2008, with a comparable antibiotic use during labour and delivery as
in our study. In their study, the incidences in total, after vaginal delivery and after elective and
emergency caesarean delivery were higher. The correlation between vaginal and caesarean
delivery was, as in other studies, larger.10 However, in comparison to the incidences in a
study7 from Israel in 2000, the incidences in our study are higher. However, in the study from
Israel, the use of prophylactic antibiotics was broader. At Uppsala University Hospital,
routine antibiotic prophylaxis is used in the event of prolonged rupture of membrane (18
hours or longer)49, preterm labour (less than 37 weeks)24, elective and emergency caesarean
deliveries50, intrapartum fever (temperature of 38.0°C or higher)23 and known GBS
colonization of the vagina24.
Our study demonstrates a strong association between manual removal of placenta after
vaginal birth and development of PPE. The association persisted in a multivariate analysis
with other potential confounding variables (adjusted OR 11.3). The result is in agreement with
a previous study of manual placental removal after vaginal birth showing an increased rate of
PPE after the procedure (adjusted OR 2.9).32 Another randomized controlled study of 62
caesarean births presented the same association (OR 8.8, p 0.05).43 In contrast to our result, a
study from 1963 presented no increased risk of PPE after manual removal of placenta.51
However, in that study, about 30% of the patients with manual removal were administered
antibiotics for unstated reasons. During manual placental removal, potential pathogenic
bacteria contaminates the uterine cavity which could be one explanation to why it is
associated with PPE. However, that would not explain the association with manual removal of
19
placenta in caesarean deliveries reported by McCurdy et al.43 The potential benefits of
antibiotic prophylaxis to prevent PPE after manual placental removal at vaginal birth have not
been investigated in any randomized controlled studies, comparing placebo or non-antibiotic
use with antibiotic prophylaxis.46
In the univariate analysis, delivery at 42 weeks or later was associated with PPE and a
tendency of an association was seen in the multivariate logistic regression analysis. There
were only 15 women with post-term deliveries in our study. The small number of women in
this group could be part of the reason to the fact that significance was not reached in the
multivariate analysis. There are few studies of the relation between post-term deliveries and
PPE but at least one has shown a significant correlation.40
Caesarean delivery is a well-studied risk factor for developing PPE and antibiotic prophylaxis
is given to women with either elective or emergency caesareans.20 Regardless of the use of
prophylactic antibiotics – routinely given intrapartum to women with caesarean deliveries in
our study population – there is still a significant association between caesarean deliveries with
a vaginal onset of labour and PPE in the univariate analysis. Significance did not persist in the
multivariate analysis. The reason for a potential remaining association despite antibiotic
prophylaxis could be that the choice of antibiotic or route of administration are not the most
adequate. There are studies comparing different routes of prophylactic antibiotics but most are
of low evidence, primarily due to limitations in study design or number of participants.52
Therefore, there might be an opportunity for future research to optimize the prophylactic
treatment.
The association between prolonged second stage of labour and risk of PPE found in the
univariate analysis, with a median twice as long in the case group, did not persist in the
multivariate analysis. Neither did any cut-off value (more than 2, 3 or 4 hours). The
association found in the univariate analysis is consistent with a study of perinatal and
maternal outcomes associated with duration of second stage in multiparous women, which
demonstrated a greater incidence of PPE after a second stage of 2 hours or longer. However,
the adjusted OR from the multivariate logistic regression in that study was not significant.53
Other studies have presented rates of maternal infection or puerperal febrile morbidity in total,
without making distinction between different infections. In these studies, significant
20
association was shown also after control for confounding variables in multivariate analysis.54–
56
Both induction of labour and oxytocin infusion were associated to PPE in our study. Since
these groups contain almost the same patients, the association to an increased risk for PPE can
be due to one or the other even a third interrelated factor. There are no studies reporting an
association between induction of labour or oxytocin use and PPE but the studies investigating
the possible correlations are few. In a study from the United States from 2013 there are no
significant association.48
Postpartum anaemia are known as a risk factor for PPE42. Level of haemoglobin was not
measured in our study, however intrapartum and postpartum blood loss were. Worldwide,
many cut-off values are used to define pathological obstetric bleeding. World Health
Organization (WHO) uses the definition of any blood loss in excess of 500 ml the first 24
hours postpartum whereas American College of Obstetricians and Gynecologists (ACOG)
defines pathological obstetric bleeding as cumulative blood of 1000 ml or more or blood loss
accompanied by signs or symptoms of hypovolemia within 24 hours.57,58 In our study we used
the cut-off value of 1000 ml since the guidelines of treatment of obstetric bleeding postpartum
uses ACOGs definition of pathological bleeding and would be the only one of clinical
importance. Bleeding of 1000 ml or more were not significantly associated with PPE.
However, that might be explained by the small number of women with a bleeding of that
volume.
Remaining clinical variables investigated in our study were not significantly associated to
PPE in the univariate analysis. For some variables the differences in incidences between
groups were clinically important although not significant in this material. Other studies have
shown significant differences for some of these variables, such as PROM, MSAF and vaginal
operative deliveries.13,37,41 The reason to the disagreements in results could be the small
number of participants in our study leading to retaining of a false null hypothesis (type-II
error).
Microorganisms in cervical cultures
There is quite a variety of microorganisms present in the cervical cultures in our study. The
relatively high prevalence of S aureus could be caused by contamination since S aureus is part
21
of the normal flora in most healthy individuals, frequently found in the skin and mucous
membranes.59 The fact that two out of five cultures containing S aureus contained another
potentially more virulent bacteria, makes S aureus an even more questionable pathogen even
if it is a major bacterial pathogen in humans at other infections. Variations in methods to
identify microorganisms could be one explanation to the different results.
In this study, we used cervical cultures to isolate potential microorganisms causing infection
since endometrial cultures were not obtained from any of the cases. Studies have shown that
microorganisms can be isolated from the cervix of 70% to 90% of afebrile women without
clinical endometritis.60,61 Therefore it is uncertain if the bacteria present in cervical cultures
are pathogenic or not, especially in cases with low-virulence microorganisms. Eschenbach et
al.60 attempted to investigate whether cervical cultures could predict the presence of
microorganisms in endometrial cultures in febrile women. Their study showed that isolation
of many facultative bacteria did not predict the presence of the same bacteria in endometrial
cultures, including the usually considered potentially virulent E coli. However, isolation of
some common virulent facultative microorganisms, including GBS and G vaginalis, and
anaerobic bacteria were associated to a relatively high predictive value. This was a small
study and therefore, the result should be viewed with caution. The conclusion of the study
was, that to isolate microorganisms from the endometrium, endometrial cultures are the most
useful culture in women with PPE and that the value of cervical cultures in these cases is
limited. The most practical alternative clinically, would be transcervical endometrial cultures.
Since cervical cultures were used in our study the results must be considered with caution.
However, the panorama of microorganisms found in our study is consistent with other studies
of microorganisms present during PPE.
Strengths and limitations
A strength of this study was that medical charts were scrutinized which enabled for control of
a large number of confounding factors and the possibility to investigate multiple exposures.
However, despite the usage of multivariate logistic regression to control for potential
confounders there might have been remaining confounders not identified in our study and
therefore not controlled for.
Our study is not without limitations. First, the cases in our study were only women with a
diagnosis of postpartum endometritis registered in the Cambio COSMIC healthcare
22
information system. Women seeking medical treatment in clinics without Cambio COSMIC
are missing. Fortunately, almost all clinics in Uppsala uses Cambio COSMIC and most
women are recommended to seek medical care at Uppsala University Hospital if
complications occur in the puerperium. Secondly, the population size is rather small which
might make the study underpowered to detect differences between groups, especially for those
variables with a small effect size or low prevalence. In a larger study, more variables would
probably show significant differences between groups. Thirdly, all data were obtained
retrospectively from medical records only. The method used in clinical work is not always the
most reliable for measuring the variables of interest. An example is the calculation of duration
of labour which is based on results of vaginal examinations. Clinically, vaginal examinations
are not performed if it is not necessary. Therefore, the exact moment of start and stop of
different stages cannot be certain. The number of vaginal examinations differs and the time
interval between is not standardized, depending on many reasons, why the inaccuracy of
duration can vary between groups. The event of missing values can also be a problem when
data is collected retrospectively, since regaining these values subsequently is not possible.
Fourthly, the study was not blinded when data were collected, why bias cannot be excluded.
However, the data of exposures were prospectively registered in the medical records, which
reduces the possible risk of bias. Most variables have little room for interpretation during
collection.
There are also some limitations regarding the observations of microorganisms potentially
causing PPE. First, because of the use of cervical cultures instead of endometrial cultures, the
predictive value of microorganisms present in the endometrium is relatively low for some
organisms. The validity of this method might therefore be low. A strength though, is that the
predictive value of other organisms associated with PPE are relatively high. Secondly, the part
of the study investigating potential microorganisms causing PPE did not have any controls
since cervical cultures were not obtained from women in the control group. This is an
inevitable error in studies of which data are collected retrospectively since there is no routine
of obtaining cervical cultures from women postpartum without signs of infections. The
consequence is that you cannot know for sure if the bacteria present in the cervical culture is
pathogenic or harmless colonisation of the vagina.
23
Conclusion In this case-control study evaluating associations between clinical variables during pregnancy
and delivery and PPE, manual removal of placenta was found independently associated with
PPE. Several other clinical variables such as post-term delivery (in gestational week 42 or
later), induction of labour, oxytocin treatment, prolonged duration of second stage and
caesarean delivery were identified to be associated in the univariate analysis. To enable
prevention, knowledge of risk factors of PPE is important and might be helpful in decisions of
interventions during labour as well as monitoring postpartum. Despite the importance of PPE
and the large number of studies, the microbiology of the infection is still not clearly defined,
mostly due to suboptimal methods to isolate bacteria in the endometrium and contamination
of cervical, vaginal and skin bacteria. This study is small, and further research is necessary to
interpret the results in practice. Larger studies are needed to identify risk factors for PPE and
well-designed randomized controlled trials with high power are needed to evaluate the value
of antibiotic prophylaxis in special events during vaginal delivery, for example in the event of
manual placental removal.
Acknowledgement
I would like to express my sincere appreciation to my supervisor Maria Jonsson for her
support, patience and professional guidance throughout this project. Thank you for sharing
your knowledge and experience in science and for your commitment and dedication to this
study and obstetrics.
24
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31
Appendix 1 – List of variables Appendix I. Definition of variables.
Variable
Definition
First vaginal delivery Nulliparas or multiparas with previous caesarean
delivery only.
Infertility treatment Egg and sperm donation, insemination, In Vitro
Fertilization and Intracytoplasmic Sperm
Injection.
Tobacco use Snuffing or smoking any time during pregnancy.
Intercurrent diseases Essential hypertonia, diabetes mellitus type 1,
thyroid disease, hepatitis, malignity, polycystic
ovary syndrome, epilepsy, systemic lupus
erythematosus, asthma, multiple sclerosis,
myoma, psychiatric diagnosis, irritable bowel
syndrome and/or Ehlers-Danlos syndromes.
Diabetes Mellitus Diabetes mellitus type 1 or gestational diabetes.
Hypertensive disorder Preeclampsia, gestational hypertension and/or
essential hypertension.
Pregnancy complications Hyperemesis, preeclampsia, gestational
hypertension, obstetric hepatosis, symphysis
pubis dysfunction, colonization of GBS,
anaemia, pruritis, fatigue, polyhydramnios,
carpal tunnel syndrome, premature contractions,
pain, bleeding, depression, thyroid disease,
growth restriction, bacterial vaginosis.
Colonization of Group B Streptococcus
(GBS)
Bacterial culture containing GBS at any time
during pregnancy.
Gestational age Calculated from obstetric ultrasonography in the
second trimester (at approximately 18 gestational
weeks).
Post-term pregnancy Gestational age of 42 weeks or longer calculated
from ultrasonography in the second trimester.
32
Induction of labour Diagnosis of induction of labour (ICD code
O61). Methods include use of amniotomy,
oxytocin treatment, Foley catheter,
prostaglandins or double-balloon catheter to
initiate active phase of labour.
Cervical ripeness of inductions Cervical ripeness was evaluated depending on
choice of method of induction. Amniotomy and
oxytocin treatment were considered favourable.
Use of Foley catheter, prostaglandins or double
balloon catheter were considered unfavourable.
Meconium-stained amniotic fluid Decided by colour of amniotic fluid.
Total duration of labour (active phase) Duration of active phase of labour retrieved from
partograms and medical charts was calculated in
minutes from a cervical dilation of 3-4 cm until
delivery of the infant.
First stage of labour The time of onset of active phase until full
cervical dilation. Retrieved from partograms and
medical charts.
Second stage of labour The time of full cervical dilation until delivery of
infant. Retrieved from partograms and medical
charts. Women not reaching second stage were
excluded.
Second stage of labour ≥3 hours Women not reaching second stage due to
caesarean section were excluded in the
univariate analysis. In the multiple logistic
regression, women not reaching second stage
were given a third value, keeping the women in
the analysis for other variables.
Bearing down effort Active phase of second stage when maternal
urge to bear down is intensified. Calculated in
minutes from mark in the partograms or text in
the medical charts until delivery of infant.
33
Uterine inertia Diagnosed by obstetrician (ICD-code O62.0 or
O62.1)
Number of vaginal examinations Number of vaginal examinations retrieved from
medical charts and partograms. The number
were corrected if midwifery or medical student
were present by multiplying the original number
by 1.5 since about half of the examinations were
done twice when a student was present (once by
the midwife and once by the student).
Blood loss Estimation of total bleeding during and after
labour until end of bleeding made by midwife
and/or obstetrician. Scaled plastic collection
bags were used to collect blood during delivery
and used pads was weighted to measure the
blood volume. If additional surgery was needed
the blood volume was measured in a similar way
and added to the previous volume. Retrieved
from medical charts.
Blood transfusion Blood transfusion given during hospital stay
after delivery.
Manual removal of the placenta Procedure when placenta is removed manually
when the placenta is not brought forth by uterine
activity. Women with caesarean deliveries were
excluded in the univariate analysis. In the
multiple logistic regression, women undergoing
caesarean section were given a third value
keeping them in the analysis for other variables.
The presented adjusted OR includes only vaginal
births.
Uterine atony Diagnosed by midwife or obstetrician.