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

3

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.

4

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.

5

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.

6

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,

8

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

9

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

10

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.