Peripartum Haemorrhage, Diagnosis and Therapy. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 015/063, March 2016)

Abstract

Purpose

This is an official interdisciplinary guideline, published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG), the Austrian Society of Gynaecology and Obstetrics (OEGGG) and the Swiss Society of Gynaecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking countries and is backed by the German Society of Anaesthesiology and Intensive Medicine (DGAI), the Society of Thrombosis and Haemostasis Research (GTH) and the German Association of Midwives. The aim is to provide a consensus-based overview of the diagnosis and management of peripartum bleeding obtained from an evaluation of the relevant literature.

Methods

This S2k guideline was developed from the structured consensus of representative members of the various professional associations and professions commissioned by the Guideline Commission of the DGGG.

Recommendations

The guideline encompasses recommendations on definitions, risk stratification, prevention and management.

I  Guideline Information

Guidelines programme of the DGGG, OEGGG and SGGG

Information on the guidelines programme is available at the end of the guideline.

Citation format

Peripartum haemorrhage, diagnosis and therapy. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 015/063, March 2016). Geburtsh Frauenheilk 2018; 78: 382–399

Guideline documents

The complete long version (in German), a PDF slideshow for PowerPoint presentations and a summary of the conflicts of interest of all the authors is available on the AWMF homepage under: http://www.awmf.org/leitlinien/detail/ll/015-063.html

Guideline authors

The following professional and scientific societies/working groups/organisations/associations have stated their interest in contributing to the compilation of the guideline text and participating in the consensus conference and nominated representatives to attend the consensus conference ( Table 1 ).

Table 1  Authors and representativity of the guideline group: participation of the target user group.

Author Mandate holder	DGGG working group/AWMF/non-AWMF professional societies/organisations/associations
Lead author and/or coordinating author:
PD Dr. med. Dietmar Schlembach	German Society of Gynaecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V. [DGGG])
Other lead authors:
Prof. Dr. med. Hanns Helmer	Austrian Society of Gynaecology and Obstetrics (Österreichische Gesellschaft für Gynäkologie und Geburtshilfe [OEGGG])
Prof. Dr. med. Wolfgang Henrich	German Society of Gynaecology and Obstetrics (DGGG)
Prof. Dr. med. Christian von Heymann	German Society of Anaesthesiology and Intensive Medicine (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin e. V. [DGAI])
Prof. Dr. med. Franz Kainer	German Society of Gynaecology and Obstetrics (DGGG)
Prof. Dr. med. Wolfgang Korte	Society of Thrombosis and Haemostasis Research (Gesellschaft für Thrombose- und Hämostaseforschung e. V. [GTH])
Prof. Dr. med. Maritta Kühnert	German Society of Gynaecology and Obstetrics (DGGG)
Dr. med. Heiko Lier	German Society of Anaesthesiology and Intensive Medicine (DGAI)
PD Dr. med. Holger Maul	Deutsche Society of Gynaecology and Obstetrics (DGGG)
Prof. Dr. med. Werner Rath	German Society of Gynaecology and Obstetrics (DGGG)
Susanne Steppat	German Society of Midwives (Deutscher Hebammenverband e. V.)
Prof. Dr. med. Daniel Surbek	Swiss Society of Gynaecology and Obstetrics (Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe e. V.[SGGG])
Prof. Dr. med. Jürgen Wacker	Germany Society of Gynaecology and Obstetrics (DGGG)

Abbreviations

AAGBI

Association of Anaesthetists of Great Britain and Ireland

AFE

amniotic fluid embolism

AMSTL

active management of third stage of labour

aPTT

activated partial thromboplastin time

AT/AT III

antithrombin/antithrombin III

BGA

blood gas analysis

BMI

body mass index

BL

blood loss

BW

body weight

CMACE

Centre for Maternal and Child Enquiries

DDAVP

desmopressin

DIC

disseminated intravascular coagulation

ESA

European Society of Anaesthesiology

FFP

fresh frozen plasma

Hb

haemoglobin

HR

heart rate

Hct

haematocrit

IM

intramuscular

INR

international normalized ratio

IU

international unit

IUFD

intrauterine fetal death

IV

intravenous

MAP

mean arterial pressure

MRI

magnetic resonance imaging

NICE

National Institute for Health and Care Excellence

OAA

Obstetric Anaesthetists Association

OR

odds ratio

PCC

prothrombin complex concentrate

POC

point of care

PPH

postpartum haemorrhage

rFVIIa

recombinant factor VII a

RBC

red blood cell concentrate

ROTEM

rotational thromboelastometry

RR _sys /RR _dia

RR systolic/RR diastolic

s/p

status post

TEG

thromboelastography

US

ultrasound

VET

viscoelastic test

WHO

World Health Organisation  

II  Guideline Application

Purpose and objectives

This aim of this guideline is to create an interdisciplinary (including anaesthesiologists and intensive care physicians, obstetricians, midwives, puerperal care nursing staff) management and treatment algorithm for the management of peripartum haemorrhage (diagnosis, risk selection, therapy).

The guideline was compiled to improve the knowledge of all persons involved in the care of pregnant women and women in childbed who experience or have an increased risk of haemorrhage.

The aim was to improve the care of affected patients and reduce problems in the management of PPH.

Targeted areas of patient care

• Outpatient care

• Primary/specialised care

• Inpatient care

Target user groups/target audience

This guideline is aimed at the following groups of people:

• gynaecologists/obstetricians in private practice (non-hospital based)

• hospital-based gynaecologists/obstetricians

• anaesthesiologists and intensive care physicians

• haemostasis specialists and lab clinicians

• interventional radiologists

• midwives

• nursing staff (surgery, anaesthesiology, intensive care unit, obstetrics/postpartum care)

Adoption of the guideline and period of validity

The validity of this guideline was confirmed in September 2015 by the respective boards/representatives of the participating professional societies/working groups/organisations/associations, by the board of the DGGG and the DGGG Guideline Commission and by the SGGG and the OEGGG, which constitutes approval of the entire contents of the guideline. This guideline is valid from May 1, 2016 through to March 31, 2019. Because of the contents of this guideline, the above-mentioned period of validity is only an estimate. The guideline can be updated earlier if urgently required. Should the guideline continue to reflect the current level of scientific knowledge, then the guidelineʼs period of validity can be extended.

III  Methodology

Basic principles

The methodology used to compile this guideline is determined by the class assigned to the guideline. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements. Guidelines are differentiated into lowest (S1), intermediate (S2) and highest (S3) class. The lowest class consists of a set of recommendations for action compiled by a non-representative group of experts. In 2004 the S2 class was divided into two subclasses: a systematic evidence-based (S2e) subclass and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.

This guideline is classified as: S2k

Grading of recommendations

The grading of evidence and the grading of recommendations was not envisaged for S2k class guidelines. Individual statements and recommendations are differentiated by syntax, not by symbols ( Table 2 ).

Table 2  Grading of recommendations.

Description of grade of recommendation	Syntax
Strong recommendation, highly binding	must/must not
Recommendation, moderately binding	should/should not
Open recommendation, not binding	may/may not

The above classification of recommendations reflects the evaluated evidence and the clinical relevance of the studies on which the recommendations are based and various measures/factors which did not appear in the grading of evidence, such as the choice of patient population, intention-to-treat or per-protocol-outcome analyses, medical or ethical behaviour towards patients, country-specific application, etc.

Statements

Expert statements included in this guideline which are not recommendations for action but simple statements of fact are referred to as statements . It is not possible to provide a level of evidence for these statements.

Achieving consensus and level of consensus

During structured consensus-based decision-making (S2k/S3 level), the authorised representatives present at the respective session vote on draft Statements and Recommendations. Discussions during the session may lead to significant changes in the wording of Statements and Recommendations. At the end of the session, the extent of agreement (level of consensus) is determined based on the number of participants ( Table 3 ).

Table 3  Classification of extent of agreement in consensus decision-making.

Symbol	Level of consensus	Extent of agreement in percent
+++	Strong consensus	> 95% of participants agree
++	Consensus	> 75 – 95% of participants agree
+	Majority agreement	> 50 – 75% of participants agree
–	No consensus	< 50% of participants agree

Expert consensus

As the name implies, this refers to consensus decisions taken with regard to specific Recommendations/Statements without a previous systematic search of the literature (S2k) or when evidence is lacking (S2e/S3). The term “Expert Consensus” (EC) used here is synonymous with the terms “Good Clinical Practice” (GCP) and “Clinical Consensus Point” (CCP) used in other guidelines. The level of recommendation is graded as previously described in the Chapter Grading of recommendations but only semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”) and without using symbols.

IV  Guideline

1  Introduction

The incidence of postpartum haemorrhage (PPH) is continually increasing 1 ,  2 ,  3 ,  4 ,  5 , mostly because of the increase in uterine atony and disorders of placental implantation and increased rates of surgical vaginal delivery and Caesarean sections and the consequent increase in primary blood loss and, in the case of Caesarean section, the increased PPH rates in subsequent pregnancies 2 ,  6 ,  7 ,  8 ,  9 ,  10 ,  11 .

In the western world, life-threatening postpartum haemorrhage occurs in approximately 2 of 1000 births and severe maternal morbidity occurs in around 3 of 1000 births 12 ,  13 ,  14 ,  15 ,  16 ,  17 ,  18 ,  19 ,  20 ,  21 ,  22 . PPH is the cause of approximately 30% of all maternal deaths in the Third World and 13% of maternal deaths in industrialised countries 21 .

The majority of maternal deaths from PPH could be avoided; major substandard care was present in 60 – 80% of all cases 1 ,  20 ,  21 ,  23 ,  24 ,  25 . What is especially alarming is that a visual estimation of blood loss during delivery results in the extent of bleeding being underestimated by 30 – 50% 26 ,  27 ,  28 ,  29 .

In Britain and America, the causes of PPH have been summarized as the “4 Ts”. (Combinations of these causes are the rule.) ( Table 4 ).

Table 4  The 4 Ts: causes of PPH 6 ,  16 ,  30 ,  31 ,  32 .

Tone (uterine atony)	Uterine distension (multiparity, polyhydramnios, fetal macrosomia) Tocolytics Precipitate labour or prolonged labour (Prolonged) oxytocin augmentation Chorioamnionitis Uterine fibroids
Tissue (placenta)	Retained placenta Abnormally invasive placenta (morbidly adherent placenta, placenta accreta/ increta/percreta) Placental remnants
Trauma	Vulvovaginal injury Cervical tear Episiotomy/perineal tear Uterine rupture Uterine inversion
Thrombin (coagulopathy)	Pregnancy-induced: Thrombocytopenia (HELLP syndrome, disseminated intravascular coagulation [DIC]) (e.g. in pre-eclampsia, intrauterine fetal death [IUFD], placental abruption, amniotic fluid embolism) Other: von Willebrand disease, plasmatic coagulopathies, thrombopathy, coagulation factor deficiencies (loss, consumption, dilution)

The main risk management problems in the management of PPH are 1 ,  24 ,  33 ,  34 :

• Delayed diagnosis and/or therapy due to underestimation of the actual amount of blood lost

• Delayed provision of blood or coagulation products

• Lack of or failure to follow simple instructions

• Lack of adequate training or advanced training

• Poor communication within the interdisciplinary team

• Deficits in the organisational structure

• Delay in initiating treatment standards

2  Definitions

Consensus-based Recommendation 2.E1
Expert consensus	Level of consensus +++
The following definition of PPH is proposed (for German-speaking areas): Blood loss of ≥ 500 ml following vaginal delivery Blood loss of ≥ 1000 ml following Caesarean section

3  Risk Stratification and Prevention

A complete and detailed patient history, ultrasound examination during antenatal appointments, assessment of the patientʼs risk of bleeding, presentation to the maternity hospital, and preparations for increased blood loss could reduce patientsʼ risk of PPH 35 .

Consensus-based Recommendation 3.E2
Expert consensus	Level of consensus +++
Location and structure of the placenta must be documented during ultrasound examination in the 2nd trimester. If necessary, patients with low-lying placenta should undergo an additional ultrasound scan to screen for vasa praevia and the findings should be documented 36 .

Consensus-based Recommendation 3.E3
Expert consensus	Level of consensus +++
An implantation disorder should be considered in women with a high-risk history (previous operations) or findings (placenta praevia) which indicate high risk.

3.1  Risk stratification and risk factors which facilitate peripartum/postpartum haemorrhage ( Table 5 )

Table 5  Risk factors for PPH 16 ,  23 ,  37 ,  38 ,  39 .

	Odds ratio or range
Blood loss	> 500 ml	> 1000 ml
Sociodemographic risk factors
obesity (BMI > 35)	1.6
maternal age (≥ 30 years)	1.3 – 1.4	1.5
Obstetric risk factors
placenta praevia	4 – 13.1	15.9
premature placental separation	2.9 – 12.6	2.6
retained placenta	4.1 – 7.8	11.7 – 16.0
prolonged expulsion of the placenta	7.6
pre-eclampsia	5.0
grand multiparity	2.3 – 4.5	2.6
s/p PPH	3.0 – 3.6
fetal macrosomia	1.9 – 2.4
HELLP syndrome	1.9
Polyhydramnios	1.9
(prolonged) oxytocin augmentation	1.8
labour induction	1.3 – 2	2.1 – 2.4
protracted labour	1.1 – 2
Surgical risk factors
emergency Caesarean section	3.6
elective Caesarean section	2.5
operative vaginal delivery	1.8 – 1.9
episiotomy	1.7 – 2.21	2.07
perineal tear	1.7	2.5
Other risk factors
antepartum haemorrhage	3.8
von Willebrand disease	3.3
anaemia (< 9 g/dl)	2.2
fever during delivery	2

Other risk factors include precipitous birth, high maternal parity, fibroids and uterine malformations 39 .

Caution: The majority of patients who develop PPH do not have identifiable risk factors 39 .

3.2  Sonographic risk stratification (placentation disorders)

Consensus-based Recommendation 3.E4
Expert consensus	Level of consensus +++
Patients with suspected abnormally invasive placenta must present early to a suitable maternity hospital where they must be treated by a multidisciplinary team (“by the best team at an optimal point in time”) 20 ,  40 .

The diagnostic value of MRI has not yet been convincingly demonstrated in these cases 41 ,  42 , but MRI examination could provide additional information when findings are ambiguous 42 ,  43 .

3.3  Prevention

3.3.1  Active management of third stage of labour

3.3.1.1  Active management after vaginal delivery

Consensus-based Recommendation 3.E5
Expert consensus	Level of consensus +++
After the infant has been born and commenced breathing, oxytocin (Syntocinon ® 3 – 5 IU slow IV infusion) must be administered for PPH prevention 44 .

Consensus-based Recommendation 3.E6
Expert consensus	Level of consensus ++
Immediate clamping of the umbilical cord at birth and controlled cord traction have no impact on reducing postpartum haemorrhage and should not be carried out.

3.3.1.2  Prevention of PPH during Caesarean section

Consensus-based Recommendation 3.E7
Expert consensus	Level of consensus +++
PPH prophylaxis must be administered as in vaginal delivery.

Prophylaxis can consist of administering either oxytocin (Syntocinon ^® 3 – 5 IU by short infusion [or slow IV infusion]) or carbetocin (Pabal ^® 100 µg) by short infusion or slow IV infusion.

3.3.2  If risk factors are present

Consensus-based Recommendation 3.E8
Expert consensus	Level of consensus +++
If risk factors are present, the following measures must be taken: Adequate venous access for every woman in labour, adequate intravenous access in case of complications of bleeding Uterotonics must be available (oxytocin, e.g. Syntocinon ® ), prostaglandins (e.g. sulprostone: Nalador ® ), misoprostol (Cytotec ® , off-label use) Check logistics: Check availability of emergency laboratory tests (complete blood count, blood gas analysis [BGA], aPTT, prothrombin time [PT] or INR, antithrombin [AT], fibrinogen, possibly thromboelastography or thromboelastometry [ROTEM]) Obstetrician and anaesthesiologist must be on site, experienced obstetrician and experienced anaesthesiologist on call Check availability of blood products: cross-matching, ordering of packed red blood cells, fresh frozen plasma and platelets Check availability of haemostatic agents (tranexamic acid [Cyclokapron ® ], fibrinogen [Haemocomplettan ® ], factor XIII [Fibrogammin ® ], recombinant activated factor VII a [rFVIIa, NovoSeven ® , off-label use]).

4  Management of PPH

Consensus-based Statement 4.S1
Expert consensus	Strength of consensus +++
Alongside general interventions (such as stabilising the patientʼs haemodynamic status), causal treatment of PPH includes medical therapy and/or surgical procedures that must be performed quickly, in a coordianted and often simultaneous manner 45 ,  46 ,  47 .

4.1  Procedures

• Measure blood loss! (Caution: blood loss in bandages, etc.)

• Rapid diagnosis of the cause of bleeding (4 Tʼs):

  • Estimation of uterine tone

  • Check whether placenta is complete (ultrasound, manual or instrumental examination)

  • Exclude vulvovaginal trauma by speculum examination

  • Administer uterotonics (in case of atony) and tranexamic acid to treat critical blood loss

  • Uterine compression

• Call in anaesthesiologist (multidisciplinary team) at an early stage

• Drug therapy and/or surgical procedures, depending on the cause of bleeding

• Control vital signs, consider timely invasive monitoring

• Initial volume substitution to maintain normovolaemia: cristalloids, in exceptional cases (e.g. acute haemorrhage and haemodynamic instability) colloidal solutions 48

• Cross-matching of blood, emergency laboratory tests (incl. full blood count, coagulation)

• Order packed red blood cells and fresh frozen plasma, provide blood products if required (delivery room, operating theatre)

• Coagulation factors, especially fibrinogen

• Other haemostatic agents (e.g. desmopressin), factor XIII or rFVIIa if necessary

• Intensive monitoring of patient during hospital stay, consider invasive monitoring

• Timely surgical intervention when conservative measures fail (see below for appropriate procedures)

Measuring blood loss

One of the cardinal problems which occur not only when defining but primarily when diagnosing and treating PPH is that the extent of postpartum blood loss is rarely measured and is known to be underestimated by 30 – 50% if assessment is done on a purely visual basis 35 ,  49 .

Consensus-based Recommendation 4.E9
Expert consensus	Level of consensus +++
Collecting all blood-soaked pads, bedding, linens and significant coagulum is strongly recommended.

5  General (Emergency) Measures and Diagnosis to Determine Causes of PPH

5.1  Atony

• Diagnosis: increased fundal height; soft slack uterus; usually intermittent heavy bleeding.

• Void the bladder!

• Mechanical procedures: uterine massage (endogenous prostaglandin formation), bimanual uterine compression (e.g. Hamiltonʼs manoeuvre)

• Exclude vulvovaginal trauma (by speculum examination and abdominal US if necessary)

• Exclude retained placenta (examine the placenta to ensure it is complete, sonography)

Consensus-based Recommendation 5.E10
Expert consensus	Level of consensus +++
Therapy: After vaginal delivery uterotonics, tranexamic acid if required careful curettage in the delivery room or operating theatre if retained placenta is suspected uterine tamponade if required other surgical procedures consider embolisation After caesarean section uterotonics, tranexamic acid if required surgical procedures

5.2  Implantation disorders

The management of abnormally invasive placenta depends on the time of diagnosis and type of delivery.

Approach for antenatal diagnosis

If an advanced implantation disorder (placenta increta, percreta) is diagnosed in the antenatal period, delivery must always be by Caesarean section.

• Extensive findings: Caesarean section with hysterectomy; alternatively, consider expectant management (e.g. delayed delivery of placenta)

• Focal findings: partial resection of the uterine wall

• If necessary carry out interventional radiology with prophylactic occlusion of the internal iliac arteries 50 ,  51

Approach for intrapartum diagnosis

• Vaginal delivery:

  • If the placenta fails to separate and bleeding is present: carry out manual separation of the placenta followed by curettage with intraoperative ultrasound monitoring, if required 52

  • If severe bleeding from the placental bed persists: carry out surgical therapy, alternatively embolisation of the uterine arteries

• Caesarean section:

  • Do not manipulate the placenta or attempt to separate it manually

  • Perform Caesarean section with hysterectomy or alternatively consider expectant management (e.g. delayed delivery of placenta)

Consensus-based Recommendation 5.E11
Expert consensus	Level of consensus ++
Therapy: After vaginal delivery uterotonics, tranexamic acid if required if necessary, manual separation of the placenta followed by curettage if necessary, uterine tamponade as a bridging procedure laparotomy and other surgical measures possibly embolisation After Caesarean section uterotonics, tranexamic acid if required surgical measures consider embolisation

5.3  Uterine inversion

Consensus-based Recommendation 5.E12
Expert consensus	Level of consensus ++
Therapy: The goal is the reposition of the uterus and treatment of the symptoms of haemorrhagic shock. The following procedures must be carried out immediately after making the diagnosis in the order stated below: Stop administration of any uterotonic drug Call in experienced obstetrician and anaesthesiologist Ensure adequate intravenous access, volume substitution Make no attempt to remove the placenta (higher blood loss); the placenta must, where possible (placenta accreta), only be removed after repositioning 53 ,  54 Attempt to reposition the fundus (Johnsonʼs manoeuvre) If attempts at repositioning are unsuccessful, administer uterine relaxants (e.g. nitroglycerin 50 µg IV, betamimetics) and repeat the attempt to reposition the uterus with Johnsonʼs manoeuvre If repositioning attempts continue to be unsuccessful → perform laparotomy and Huntingtonʼs procedure, simultaneously with Johnsonʼs manoeuvre if necessary; if attempts are still unsuccessful, perform the Haultain procedure Administer uterotonics (e.g. oxytocin) after successful repositioning Provide antibiotic protection (e.g. cephalosporin or clindamycin)

6  Medication and Surgical Measures to Treat PPH

6.1  Uterotonics

6.1.1  Oxytocin (Syntocinon ^® ) IV (IM if necessary)

Consensus-based Recommendation 6.E13
Expert consensus	Level of consensus +++
A maximum of 6 IU undiluted oxytocin can be administered slowly and intravenously: 3 – 5 IU (1 vial) in 10 ml NaCl 0.9% as a single (slow intravenous!) bolus If necessary, this can be followed by 10 – 40 IU oxytocin in 500 – 1000 ml saline as a continuous infusion (dose depends on the clinical situation, particularly the impact on uterine tone) 16 ,  55 .

The onset of action after IV administration (half-life of 4 – 10 min) is less than one minute or 3 – 5 minutes following intramuscular administration (maximum 10 IU).

6.1.2  Carbetocin (Pabal ^® )

The use of carbetocin to treat PPH is currently not yet been sufficiently investigated. The use of carbetocin to treat PPH has been reported in individual cases.

6.1.3  Methylergometrine (Methergin ^® )

Consensus-based Recommendation 6.E14
Expert consensus	Level of consensus +++
Given the range of serious side effects and the fact that better alternatives are available, the utmost caution is advised when administering methylergometrine to manage postpartum haemorrhage.

Consensus-based Recommendation 6.E15
Expert consensus	Level of consensus ++
Methylergometrine should not be administered as an intravenous bolus.

6.1.4  Prostaglandins

Consensus-based Recommendation 6.E16
Expert consensus	Level of consensus +++
If first-line uterotonics are not effective and patients do not respond to first-line uterotonics, prostaglandins must be administered immediately 56 .

Consensus-based Recommendation 6.E17
Expert consensus	Level of consensus +++
Oxytocin receptor agonists and prostaglandins must not be administered simultaneously.

Consensus-based Statement 6.S2
Expert consensus	Level of consensus ++
Note: Postpartum uterine atony and uterine haemorrhage are life-threatening pathologies and an urgent indication for the administration of prostaglandin derivatives if no other alternatives are available or oxytocin is not effective, until patients can receive obstetric/gynaecological treatment. In this situation the side effects and contraindications must be carefully considered (benefits and drawbacks weighed up). Close haemodynamic monitoring is necessary when prostaglandin derivatives are administered.

6.1.4.1  Sulprostone (Nalador ^® )

Dosage:

• 1 vial = 500 µg in 500 ml solution administered via an infusion pump

• Initial dose: 100 ml/h, up to a maximum of 500 ml/h if required

• Maintenance dose: 100 ml/h

• Maximum dose 1000 µg/10 hours (2 vials)

• Maximum daily dose 1500 µg (3 vials)

6.1.4.2  Misoprostol (Cytotec ^® )

Dosage: 800 – 1000 µg misoprostol administered rectally or 600 µg administered orally 57  –  60 .

A Cochrane meta-analysis showed that oxytocin infusion was more effective as a first-line therapy than the administration of misoprostol and additionally had fewer side effects. When used after prophylactic uterotonics, misoprostol and oxytocin were equally effective 61 .

Consensus-based Statement 6.S3
Expert consensus	Level of consensus +++
Note: Because of its delayed onset of action and the availability of better and approved alternatives, misoprostol is not suitable to treat persistent PPH. The use of misoprostol to treat moderately persistent PPH after the administration of oxytocin may be considered (off-label use!). However, the current data is still insufficient to make a final recommendation.

Consensus-based Statement 6.S4
Expert consensus	Level of consensus +++
Note: Postpartum uterine atony and uterine haemorrhage are life-threatening pathologies and the administration of misoprostol is urgently indicated if no other alternatives are available, until patients can receive obstetric/ gynaecological treatment. In this context the side effects and contraindications must be carefully considered (benefits and drawbacks weighed up). Close haemodynamic monitoring is essential when misoprostol is administered.

6.1.4.3  Intrauterine application of prostaglandins

Consensus-based Statement 6.S5
Expert consensus	Level of consensus +++
The intramyometrial application of sulprostone (e.g. to the uterine fundus in cases with caesarean section) is contra-indicated 56 .

7  Uterine Tamponade

The objective of uterine cavity tamponade is twofold: to treat PPH (i.e., to achieve definitive haemostasis) and as a “bridging” measure (i.e., to achieve temporary haemostasis and haemodynamic stabilisation and allow other measures [surgical or interventional radiology] to be put in place) 62 ,  63 ,  64 . In addition to other second-line treatment strategies, uterine tamponade can significantly reduce the rate of emergency hysterectomies 65 ,  66 .

In addition to tamponade strips, there are a number of different balloon tamponade systems available for uterine tamponade; their efficacy has been described in various publications and their use has the advantage of allowing the early detection of persistent bleeding 64 ,  67 ,  68 ,  69 ,  70 ,  71 ,  72 ,  73 .

Consensus-based Recommendation 7.E18
Expert consensus	Level of consensus ++
Parallel administration of uterotonics Vaginal examination/ultrasound (to exclude trauma, retained placenta, clot evacuation) Bladder catheter Use a liquid (0.9% saline, body temperature if possible) to fill the balloon tamponade – NOT air Additional vaginal tamponade Intensive monitoring, antibiotic prophylaxis Can be left in utero for up to 24 hours

There has been a recent report on the use of a special gauze (Celox ^® ) coated with a haemostatic agent (chitosan), originally developed for emergency treatment and military combat medicine, to successfully manage PPH 74 .

Consensus-based Recommendation 7.E19
Expert consensus	Level of consensus ++
Uterine tamponade – in whatever form – does not preclude other necessary therapeutic options, such as compression sutures 64 ,  75 ; the use of compression sutures is strongly recommended, particularly to treat atony 75 ,  76 ,  77 ,  78 .

8  Surgical Measures (Compression, Devascularisation, Hysterectomy) and Embolisation

8.1  Bridging procedures

Consensus-based Recommendation 8.E20
Expert consensus	Level of consensus ++
In the event of the lethal triad consisting of persistent haemorrhage, haemorrhagic shock und coagulopathy, the following three-stage approach is recommended 62 : Early surgical haemostasis carried out by the attending surgical obstetrician using a Pfannenstiel incision or median laparotomy, eventeration of the uterus with cranial traction and uterine compression, and atraumatic clamping of the uterine arteries to minimise perfusion. Placement of uterine compression sutures and application of a uterine tamponade. Parallel correction of hypovolaemia, temperature, disturbed acid-base balance and coagulopathy by the anaesthesiologist; if possible, surgery should then be paused until stabilisation. Definitive (surgical) treatment of the now haemodynamically stable patient by a surgeon with the appropriate surgical expertise. If the necessary infrastructure is available, option to perform interventional radiological embolisation of afferent uterine arteries 79 ,  80 . The benefit of this approach is that it can preserve fertility, as has been described for large case series 81 ,  82 ,  83 ,  84 .

8.2  Uterine compression sutures

The aim of these sutures is to compress the uterus, reduce the placental adhesion area and tamponade the bleeding site. This approach is indicated for uterine bleeding after vaginal delivery or following Caesarean section. At present it is not possible to say anything about the optimal efficacy of specific types of sutures. All of the employed methods had high success rates in terms of preventing hysterectomy which would otherwise have been necessary. The choice of the appropriate suture method depends on the indication (atony, bleeding from the placental bed, diffuse bleeding) 85 .

Consensus-based Recommendation 8.E21
Expert consensus	Level of consensus +++
Suitable suture materials (large needles, long suture threads) must be kept in readiness in the operating theatre.

8.3  Vascular ligatures

In addition to simple ligature of the uterine artery 86 stepwise uterine devascularisation can also be used for haemostasis. The technique consists of 5 consecutive steps to ligate the ascending and descending branches of the uterine arteries and the ovarian arterial collaterals 87 ,  88 .

Consensus-based Recommendation 8.E22
Expert consensus	Level of consensus +++
Ligature of the internal iliac artery must only be carried out as a last resort and only by a surgeon with extensive experience of pelvic surgery.

8.4  Postpartum hysterectomy

Consensus-based Recommendation 8.E23
Expert consensus	Level of consensus +++
Conservative measures to preserve the uterus are only useful if the patient is haemodynamically stable and does not have life-threatening bleeding 89 ,  90 . The decision that hysterectomy is indicated must not be delayed or left too late.

Consensus-based Recommendation 8.E24
Expert consensus	Level of consensus +++
Supracervical hysterectomy is the procedure of choice for atony, as the operating time is significantly shorter and the operation does not lead to unintended vaginal shortening. Total hysterectomy should be considered for placental implantation disorders of the lower uterine segment; visualisation of the ureters during this procedure is recommended.

Relative contraindications for uterus-preserving measures are:

• Extensive abnormally invasive placenta (placenta increta/percreta) where the placental implantation bed is open, bleeding from the placental implantation bed is resistant to treatment or the implantation bed covers large areas of the uterine wall.

• Non-reconstructable uterine injury

• Septic uterus

Consensus-based Recommendation 8.E25
Expert consensus	Level of consensus ++
During the bridging time to definitive treatment, (bimanual) compression of the aorta for up to 20 minutes may be carried out to avoid unnecessary blood loss 91 ,  92 . If it is clear that the haemorrhage cannot be controlled by hysterectomy or is continuing even though hysterectomy has been carried out, the lesser pelvis and abdomen should be packed with sufficient moistened abdominal cloths.

8.5  Arterial catheter embolisation

Consensus-based Recommendation 8.E26
Expert consensus	Level of consensus +++
Every obstetric department should ascertain whether arterial catheter embolisation can be performed in their facility and the time it takes for this method to be available and then create the organisational structure which will determine at what point the patient should be transferred to the interventional radiology department. The precondition for transfer is that the patient is haemodynamically stable and does not have massive bleeding.

Consensus-based Recommendation 8.E27
Expert consensus	Level of consensus ++
If catheter embolisation is available on site, the radiologist should be notified early (e.g. when an attempt at haemostasis using uterine compression sutures is unsuccessful). Because of the range of side effects, medical and surgical treatment options should be largely exhausted. The time of transfer to the radiology department is also determined by how important it is to preserve the uterus.

Consensus-based Recommendation 8.E28
Expert consensus	Level of consensus +++
Before the patient is transferred, intra-abdominal packing should be considered as a bridging procedure if the patient has just undergone a hysterectomy procedure to prevent a critical loss of blood during transportation and contain the bleeding during the sometimes protracted intervention.

Consensus-based Recommendation 8.E29
Expert consensus	Level of consensus ++
If the intervention can be planned ahead (e.g., placenta increta/percreta), endovascular catheters can already be placed preoperatively into the internal iliac artery on both sides.

Catheter embolisation may be used as a last resort to treat persistent diffuse bleeding in the lesser pelvis after postpartum hysterectomy 93 .

9  Haemostasis and Coagulation Management – Intensive Medical Procedures

9.1  Background

Understanding and recognising the most probable pathophysiology of the bleeding is important, as this will offer pointers for different therapeutic approaches. The problem associated with haemostatic management is the difficulty in differentiating between increased bleeding caused by a major injury and protracted bleeding where the composition of blood has changed (i.e., the normal capacity of the system to compensate for smaller injuries has been reversed; this equates to an impairment of the coagulation system = coagulopathy). It is therefore necessary to distinguish between:

• trauma-induced coagulopathy with shock and massive tissue trauma

• initial “traumatic” haemorrhage caused by tissue trauma, and

• initial coagulopathic bleeding.

Impaired coagulation (= coagulopathy) is often an early pathology of PPH which can occur before dilutional coagulopathy occurs 39 ,  94 .

Consensus-based Recommendation 9.E30
Expert consensus	Level of consensus +++
The length of time needed to obtain diagnostic findings means that it is not possible to await the results of diagnostic procedures which differentiate between different coagulopathies (e.g. congenital vs. acquired) before making treatment decisions. As a rule (if the patientʼs medical history does not indicate any congenital coagulopathy), it should be assumed that patients with peripartum or postpartum haemorrhage have an acquired coagulopathy, unless a surgical cause of haemorrhage can be clearly identified.

It is also important to take account of the fact that, because of the associated dilution effect and the use of coagulation factors, every primary mechanical bleeding treated with volume replacement and fresh frozen plasma (FFP) will become coagulopathic if volume substitution and FFP administration is continued over a lengthy period 95  –  97 .

Consensus-based Statement 9.S6
Expert consensus	Level of consensus +++
It is therefore essential that all hospitals with obstetric departments develop a treatment algorithm for peri-/postpartum haemorrhage which is adapted to the specific conditions in the respective hospital 46 ,  98 ,  99 ,  100 ,  101 . The aim must be to identify haemorrhaging patients early on and describe the appropriate interdisciplinary surgical, interventional and haemostatic treatment to manage the bleeding. This algorithm should define the approach for the treatment process based on the clinical situation and take account of all available treatment options (pharmacological therapies, interventional procedures, surgical interventions).

9.2  Options to treat peri-/postpartum coagulopathic haemorrhage

Consensus-based Statement 9.S7
Expert consensus	Level of consensus +++
During active bleeding, any iatrogenic aggravation of the tendency to bleed (e.g. by administering artificial colloids for volume replacement which has a strong dilution-related coagulopathic effect, or attempt to achieve high-normal blood pressure) should be avoided, where possible.

Consensus-based Statement 9.S8
Expert consensus	Level of consensus ++
Blood component therapy is currently the standard therapy for haemostasis, either using labile (cellular components, FFP) or stable (lyophilised factor concentrates) blood products, and should be administered early to prevent dilutional coagulopathy occurring in addition to the already existing loss of blood.

Based on the current state of knowledge, f ibrinogen plays a key role. In patients with a history of peri-/postpartum haemorrhage and patients with peripartum bleeding, plasma fibrinogen concentrations should be determined (irrespective of treatment), as concentrations < 2 g/l could help identify those patients at increased risk of severe PPH 39 ,  46 .

Consensus-based Recommendation 9.E31
Expert consensus	Level of consensus ++
In any case, potentially increased fibrinolytic activity should be treated by the administration of tranexamic acid (an antifibrinolytic) before the substitution of fibrinogen (factor concentrate or FFP) is considered 39 .

Consensus-based Statement 9.S9
Expert consensus	Level of consensus +++
The beneficial effects (lower loss of blood, reduced blood transfusion, increased Hb, lower number of invasive procedures) of administering tranexamic acid to treat PPH have since been shown in randomised, controlled studies of around 2000 patients 102 ,  103 ,  104 ,  105 ,  106 ,  107 ,  108 ,  109 ,  110 . In 2013 the ESA issued a strong recommendation based on moderate evidence for the administration of tranexamic acid to treat obstetric bleeding to reduce blood loss, bleeding duration and the number of transfusions 46 . There are no reliable data on the use of DDAVP (Minirin ® ) in obstetrics which would permit an evidence-based recommendation 111 , although there have been repeated reports of observational studies with positive outcomes 112 . According to the ESA, DDAVP may be useful to treat platelet function disorders resulting from acquired von Willebrand syndrome (from drugs, acidosis, hypothermia) 46 .

Consensus-based Recommendation 9.E32
Expert consensus	Level of consensus +++
Although the data is controversial and prospective randomised studies are lacking, one or two attempts at treatment with rFVIIa at a dose of 90 µg/kg BW can be undertaken as a last resort in carefully selected cases if the patient has previously received adequate and appropriate treatment with other blood products, the other methods used for haemostasis were not sufficiently effective, and the patient still wants to have other children before undergoing a hysterectomy 39 ,  113 ,  114 ,  115 ,  116 . Because of the risk of thromboembolism, recombinant FVIIa (NovoSeven ® ) should only be given as a last resort 117 . Plasmatic factor concentrations and platelet numbers should be optimised before rFVIIa is administered 46 .

Consensus-based Statement 9.S10
Expert consensus	Level of consensus ++
In summary, the conclusions to be drawn from the currently available data on haemostatic management recommend an escalating concept (i.e., a successive step-by-step range of treatment options) adapted to the respective conditions in each hospital 46 ,  99 ,  100 , early administration of tranexamic acid, preferably immediately after making the diagnosis, stabilisation of physiological preconditions for coagulation (i.e. pH, temperature, calcium level) 46 ,  95 , if bleeding persists, viscoelastic test or conventional diagnostic tests to diagnose the cause of bleeding, if bleeding persists and substitution is required (if need be, in parallel to other mechanical forms of treatment), early replacement of coagulation factors with factor concentrates and/or FFP (fibrinogen should be considered if dilutional coagulopathy is present, otherwise PCC and F XIII may be used), if necessary (i.e. when other approaches are not effective), optimisation of platelet numbers (target > 100,000/µl for patients with active bleeding requiring transfusion) 46 .

Consensus-based Recommendation 9.E33
Expert consensus	Level of consensus +++
After the underlying cause of bleeding has been treated, thromboprophylaxis must be administered within 24 hours 39 . Because of the reduced antithrombin activity (absolute activity may even be less than 0.5 kIU/l) in the majority of women with PPH, an increased risk of thromboembolism is expected after the bleeding has stopped 118 . After the administration of individual coagulation factor concentrates or complex preparations (e.g. PCC), antithrombin activity can be determined on the intensive care unit and substituted if necessary 119 . The target value is ≥ 80% or ≥ 0.8 kIU/l 119 ,  120 ,  121 .

9.3  Anaesthesia-related aspects of managing PPH

Consensus-based Recommendation 9.E34
Expert consensus	Level of consensus +++
Maintain or achieve haemodynamic stability and normovolaemia: myocardiac ischaemia with reduced contractility is often present when Hb values ≤ 6 g/dl (3.726 mmol/l) with or without haemodynamic abnormality (RR sys  < 90 mmHg and/or RR dia  < 50 mmHg and/or HR ≥ 115/min) 122 ,  123 . Timely call for expert assistance is recommended for uncontrolled blood loss of more than 500 ml following vaginal delivery or more than 1000 ml following Caesarean section and is essential if blood loss is more than 1500 ml 29 ,  89 ,  95 ,  124 . For patients receiving regional anaesthesia (spinal anaesthesia, epidural anaesthesia): if blood loss is ≥ 1500 – 2000 ml and there are signs of persistent bleeding: secure the airway and ensure sufficient oxygen supply ; if necessary, perform early intubation after consultation with the surgeon 125 . If there is a loss of protective reflexes, endotracheal intubation to secure the airway and ensure sufficient oxygenation must take priority. Place wide-diameter access points (2× ≥ 16 G) followed by arterial blood pressure measurement, if necessary even before intubation. A wide-diameter central access (≥ 9 Fr) is recommended 125 ,  126 ,  127 ,  128 . Cell saver blood (official recommendations of CMACE, NICE, OAA/AAGBI, ESA): use of mechanical autotransfusion in patients undergoing elective Caesarean section (e.g. in cases with placenta increta/percreta) can reduce the administration of allogenic blood postoperatively and the duration of hospital stay 129 ,  130 . In the emergency setting of PPH the following caveats must be taken into consideration: should only be used, after amniotic fluid removal and delivery of the neonate. Cell-saver blood does not contain clotting factors or platelets. Coagulation factors should be substituted to prevent coagulopathy when administering high transfusion volumes 131 . Cases of hypotension have been reported following the re-transfusion of cell-saver blood with a leukocyte depletion filter 132 . Target values in haemodynamic therapy for “healthy” pregnant women and strong bleeding: After cord clamping, hypotensive resuscitation until surgical haemostasis is achieved with restrictive fluid therapy 133 ,  134 . “Normal recapillarisation time” or “palpable radial pulse” are the target values for volume replacement therapy 135 ,  136 Goal: MAP > 65 mmHg or lower 137 or RR sys  ~ 90 mmHg 138 . Target Hb: indication for blood transfusion until surgical haemostasis: 7 g/dl (4.347 mmol/l); after surgical haemostasis and successful treatment of the underlying pathology: 7 – 9 g/dl (4.347 – 5.589 mmol/l) 23 ,  134 ,  138 . Note: ensure sufficient additional iron supplementation on the ward postoperatively. Pharmacological thromboprophylaxis within 24 hours after the pathology causing the bleeding has been treated 134 .

Escalating regimen of haemostatic therapeutic options to treat PPH (based on recommendations of the S3-guideline 012/019 “Polytrauma/Schwerverletztenbehandlung” [Multitrauma/Treatment of Severely Injured Persons], DGAI recommendations on treating severe bleeding and ESA recommendations on treating perioperative haemorrhage) 100 ,  136 .

1.	Stabilise general conditions (prophylaxis and therapy!)	Core temperature ≥ 34 °C (preferably normothermia) pH ≥ 7.2 ionised Ca ++ concentration > 0.9 mmol/l (preferably normocalcaemia)
2.	Prevent potential (hyper-) fibrinolysis (always PRIOR to the administration of fibrinogen and/or FFP!)	Tranexamic acid (Cyklokapron ® ) initially 1 – 2 g (15 – 30 mg/kg BW), repeat as needed
3.	Substitution of oxygen carriers	RBC administration Haemostatic target in patients with severe bleeding: Hb ~ 7 – 9 g/dl (4.3 – 5.5 mmol/l) or Hct ~ 30%
4.	Substitution of clotting factors (if severe haemorrhage persists) depending on availability in hospital	FFP ≥ 20 (preferably 30) ml/kg BW or/and fibrinogen (Haemocomplettan ® ) (2–)4(–8) g (30 – 60 mg/kg BW) Target: ≥ 200 mg/dl or ≥ 2.0 g/l
	Patients who require (or are anticipated to require) massive transfusion or suffer life-threatening haemorrhagic shock may benefit from high FFP : RBC ratio of ≥1 : 2 or from combined administration of FFP and factor concentrates.	If required, PCC initially 1000 – 2500 IU (25 IU/kg BW)
		If required, 1 – 2×FXIII (Fibrogammin ® P) 1250 IU (15 – 20 IU/kg BW)
	and (if thrombocytopenia is suspected) increased platelet adhesion to endothelium + release of von Willebrand factor and FVIII from endothelium/liver sinusoids (→ agonist for vasopressin type 2 receptor)	DDAVP = desmopressin (Minirin ® ) 0.3 µg/kg BW over a period of 30 minutes (1 vial per 10 kg BW over a period of 30 min)
5.	Platelet substitution for primary haemostasis	Platelet concentrate (target for haemorrhage requiring transfusion: 100 000/µl)
6.	If necessary, thrombin burst with platelet and coagulation activation (consider general haemostatic conditions!)	In individual cases and when all other treatment options have been unsuccessful rFVIIa (NovoSeven ® ) if required, initially 90 µg/kg BW
	During ongoing bleeding	No antithrombin (ATIII) during haemorrhage , may be considered after administration of PCC and cessation of bleeding No heparin during haemorrhage
	CAUTION: Thrombosis prophylaxis is mandatory within 24 hours after cessation of the pathology causing the bleeding!

9.4  Rotational thromboelastometry (ROTEM)/thromboelastography (TEG)

The mean time until the results of standard laboratory parameters are available in the operating room is at least 45 minutes 139 . Coagulation disturbances can be detected significantly faster with the viscoelastic test (VET) 139 ,  140 .

Currently, two procedures are used for point-of-care (POC) diagnostics offering prompt, bedside recognition of clotting disorders based on VET: rotational thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany) and thromboelastography (TEG, Haemonetics, Braintree, MA, USA) 141 .

At present there are no class 1 recommendations on the use of these procedures 46 .

10  Transportation

Consensus-based Recommendation 10.E35
Expert consensus	Level of consensus +++
As transporting a haemodynamically instable patient is a serious risk, any transportation of such patients as part of the management of PPH must be carefully weighed up, quite apart from the organisational conditions at the facility caring for the patient (or transportation should only be considered after haemodynamic stabilisation). It is important that the facility transferring the patient and the facility accepting the patient agree about timing and staff coverage during transportation of the patient in the run-up to the patient transfer and record what the two facilities have agreed upon in writing 142 .

11  Monitoring after PPH

Consensus-based Recommendation 11.E36
Expert consensus	Level of consensus +++
Following PPH, individually adapted active monitoring must be carried out for at least 24 hours.

12  Documentation

Consensus-based Recommendation 12.E37
Expert consensus	Level of consensus +++
Every event defined as an emergency must be carefully documented. It is recommended to use the special forms developed for the respective organisational unit for documentation.

13  Debriefing

Consensus-based Recommendation 13.E38
Expert consensus	Level of consensus +++
Interdisciplinary team debriefing is recommended.

14  Training

Consensus-based Recommendation 14.E39
Expert consensus	Level of consensus +++
Simulations of haemorrhagic situations must be carried out by an interdisciplinary team at regular intervals; studies have shown that this leads to an improvement in the management of peri-/postpartum haemorrhage 35 ,  143 .

Guideline Program. Editors.

Leading Professional Medical Associations

German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V. [DGGG]) Head Office of DGGG and Professional Societies Hausvogteiplatz 12, DE-10117 Berlin info@dggg.de http://www.dggg.de/

President of DGGG Prof. Dr. Birgit Seelbach-Göbel Universität Regensburg Klinik für Geburtshilfe und Frauenheilkunde St. Hedwig-Krankenhaus Barmherzige Brüder Steinmetzstraße 1–3, DE-93049 Regensburg

DGGG Guidelines Representative Prof. Dr. med. Matthias W. Beckmann Universitätsklinikum Erlangen, Frauenklinik Universitätsstraße 21–23, DE-91054 Erlangen

Prof. Dr. med. Erich-Franz Solomayer Universitätsklinikum des Saarlandes Geburtshilfe und Reproduktionsmedizin Kirrberger Straße, Gebäude 9, DE-66421 Homburg

Guidelines Coordination Dr. med. Paul Gaß, Christina Fuchs, Marion Gebhardt Universitätsklinikum Erlangen Frauenklinik Universitätsstraße 21–23 DE-91054 Erlangen fk-dggg-leitlinien@uk-erlangen.de http://www.dggg.de/leitlinienstellungnahmen

Austrian Society of Gynecology and Obstetrics (Österreichische Gesellschaft für Gynäkologie und Geburtshilfe [OEGGG]) Innrain 66A, AT-6020 Innsbruck stephanie.leutgeb@oeggg.at http://www.oeggg.at

President of OEGGG Prof. Dr. med. Petra Kohlberger Universitätsklinik für Frauenheilkunde Wien Währinger Gürtel 18–20, AT-1180 Wien

OEGGG Guidelines Representative Prof. Dr. med. Karl Tamussino Universitätsklinik für Frauenheilkunde und Geburtshilfe Graz Auenbruggerplatz 14 AT-8036 Graz

Prof. Dr. med. Hanns Helmer Universitätsklinik für Frauenheilkunde Wien Währinger Gürtel 18–20, AT-1090 Wien

Swiss Society of Gynecology and Obstetrics (Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe [SGGG]) Gynécologie Suisse SGGG Altenbergstraße 29, Postfach 6, CH-3000 Bern 8 sekretariat@sggg.ch http://www.sggg.ch/

President of SGGG Dr. med. David Ehm FMH für Geburtshilfe und Gynäkologie Nägeligasse 13 CH-3011 Bern

SGGG Guidelines Representative Prof. Dr. med. Daniel Surbek Universitätsklinik für Frauenheilkunde Geburtshilfe und feto-maternale Medizin Inselspital Bern Effingerstraße 102 CH-3010 Bern

Prof. Dr. med. René Hornung Kantonsspital St. Gallen, Frauenklinik Rorschacher Straße 95, CH-9007 St. Gallen