Fibrinogeen bij vrouwen met bloedverlies van 500 mL of meer postpartum
Uitgangsvraag
Wat is de rol van vroege fibrinogeen suppletie bij vrouwen postpartum met aanhoudend bloedverlies van 500 mL of meer?
Aanbeveling
Aanbeveling-1
Geef géén fibrinogeenconcentraat in de vroege behandeling van vrouwen met aanhoudend bloedverlies van 500 mL of meer postpartum.
Voor de identificatie van risicofactoren voor HPP en de behandeling van HPP wordt verwezen naar de Fluxus Implementatie Strategie en naar het modelprotocol behandeling van HPP.
Aanbeveling-2
Overweeg toediening van fibrinogeenconcentraat bij vrouwen met aanhoudend bloedverlies meer dan 1500 mL postpartum, zo mogelijk op geleide van laboratoriumafwijkingen passend bij een fibrinogeentekort en streef daarbij naar een fibrinogeenactiviteit >2g/L.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
De werkgroep heeft een literatuurstudie verricht naar de (on)gunstige effecten van vroege toediening van fibrinogeen vergeleken met geen toediening van fibrinogeen of placebo bij vrouwen met >500 mL postpartum bloedverlies na een vaginale baring of sectio. Op basis van de resultaten van één systematische literatuur review en één randomized controlled trial lijken er geen klinisch relevante verschillen te zijn in de cruciale uitkomstmaten bloedverlies, maternaal overlijden en bloedtransfusie, of de belangrijke uitkomstmaten hysterectomie, overige hemostatische interventie, overdracht naar meer intensieve zorg (IC, medium care afdeling en bijwerkingen, tussen toediening van fibrinogeen en placebo of geen toediening van fibrinogeen. Er zijn geen verschillen gerapporteerd m.b.t. de cruciale uitkomstmaten shock en orgaandisfunctie, en m.b.t. de belangrijke uitkomstmaten coagulopathie, gevoel van welzijn voor de vrouw, aanvaardbaarheid, tevredenheid over de interventie en borstvoeding. De bewijskracht werd beoordeeld als ‘laag’ voor bloedverlies vanwege imprecisie en risico op bias of gebrek aan generaliseerbaarheid. De bewijskracht voor hysterectomie, maternaal overlijden, bloedtransfusie, overige hemostatische interventie, overdracht naar hoger zorgniveau en bijwerkingen werd beoordeeld als ‘zeer laag’ vanwege gebrek aan generaliseerbaarheid en imprecisie. Voor shock, orgaandisfunctie, coagulopathie, overige hemostatische interventie, overdracht naar intensievere zorg, gevoel van welzijn voor de vrouw, aanvaardbaarheid, tevredenheid over de interventie en borstvoeding werd geen literatuur gevonden en werd de bewijskracht beoordeeld met ‘geen GRADE’.
Er lijkt o.b.v. de twee geïncludeerde RCTs geen rol te zijn voor het vroeg empirisch toedienen van fibrinogeenconcentraat aan vrouwen met bloedverlies van meer dan 500 mL. Hierbij dient te worden aangetekend dat de incidentie van hypofibrinogenemie (<2g/L) zeer laag was in deze studies (<2%). Abnormale stollingswaarden (APTT/PT) komen zelden voor bij HPP <4 liter en normale EXTEM CT of koaline r tijden bij ROTEM/TEG hebben een hoge negatief voorspellende waarde voor APTT/PT verlenging (Bell 2023). Dit betekent dat ook bij >2000 mL bloedverlies nog bij meer dan 80% van de kraamvrouwen normale stollingswaarden behouden blijven en daarmee routinematig behandelen niet te adviseren is. In verband met de spontane stijging van stollingsfactoren gedurende de zwangerschap, piekend rondom de bevalling, is hypofibrinogenemie een laat symptoom bij verbruiks- dan wel verdunningscoagulopathie postpartum. Naast hypofibrinogenemie zullen in dergelijke gevallen ook andere stollingsfactoren verlaagd zijn en is stollingscorrectie m.b.v. plasma volgens een massaal bloedverlies transfusieschema of cryoprecipitaat mogelijk rationeler dan suppletie met alleen fibrinogeen. Verbruiks- dan wel verdunningscoagulopathie leidt immers niet tot één maar tot meerdere stollingsfactor deficiënties. Het kleine volume en de snelle beschikbaarheid van fibrinogeenconcentraat zijn voordelen t.o.v. plasma of cryoprecipitaat. De huidige literatuur geeft echter aanwijzingen dat profylactische toediening van fibrinogeen medisch en kostentechnisch géén voordelen biedt t.o.v de standaard behandeling bij HPP. Subgroep analyses van de OBS2 trial suggereren dat fibrinogeenconcentraat niet nodig is bij Fibtem >12mm of fibrinogeen >2 g/l (Collins 2017).
In de zeldzame situatie van Acute Obstetrische Coagulopathie (AOC) – zoals kan voorkomen bij IUVD of abruptio placentae- is de situatie anders omdat dit gedreven wordt door zeer laag functioneel fibrinogeen, hetgeen zich vertaalt in sterk afwijkende TEG MA/FIBTEM A5 waarden, afwijkende stoltijden (APTT/PT) en een sterk verhoogde d-dimeer door hyperfibrinolyse. (Bell 2023) Abruptio placentae is de meest voorkomende obstetrische oorzaak van hypofibrinogenemie a.g.v. stollingsfactor consumptie in combinatie met bloedverlies. Ernstige hypofibrinogenemie kan ook voorkomen t.g.v. acute vruchtwaterembolie (Vermeulen Best Pract & Res Clin Anest 2002).
Congenitale hypofibrinogenemie is een andere -zeldzame- uitzondering waarbij preventief toedienen van fibrinogeenconcentraat geïndiceerd kan zijn; zoals vastgelegd in een vooraf op te stellen partusplan in overleg met de hemofiliebehandelaar (Hugon-Rodin 2023).
Behandeling met fibrinogeenconcentraat brengt een zeer klein risico op trombose met zich mee (gerapporteerd <0.01%). Daarentegen worden koortsreacties relatief vaak gezien (>10%) en soms allergische of anafylactische reacties (0,1-1%). De halfwaardetijd van fibrinogeen is relatief lang in vergelijking met andere stollingsfactoren (gemiddeld 79 uur).
De startdosis van fibrinogeenconcentraat bij de behandeling van HPP is in het algemeen 2-4 gram iv., op geleide van de fibrinogeen activiteit (streef naar >2g/L). In zeer ernstige gevallen, zoals bij AOC, kan een hogere dosis (4-8 gram) nodig zijn.
Andere stollingsfactor producten zoals Protrombine Complex Concentraat (geconcentreerd uit plasma gewonnen vitamine K afhankelijke stollingsfactoren II, VII, IX en X) of recombinant Factor VIIa concentraat (rFVIIa) zijn in uitzonderlijke gevallen ook toegepast, echter de bewijslast is hiervoor lager t.o.v. fibrinogeenconcentraat. In 2022 heeft de EMA (Europees Medicijn Agentschap) de indicatie ernstige HPP niet responderend op behandeling met uterotonica toegekend voor o.b.v. 1 gerandomiseerde open label klinische studie met aanwijzingen dat in de rFVIIa studiearm minder vaak invasieve procedures werden verricht. Dit effect kon in een latere meta-analyse niet worden bevestigd. Voor de veiligheid van beide middelen in de setting van acute aanhoudende HPP is onvoldoende bewijs.
Waarden en voorkeuren van patiënten (en evt. hun verzorgers)
Fibrinogeenconcentraat wordt bereid uit normaal humaan plasma. Voor sommige zwangere vrouwen is het belangrijk dat tijdens de intake wordt besproken dat zij vanwege bepaalde (geloofs)overtuigingen het gebruik van bloedproducten afwijst. In dit gesprek moet worden besproken hoe de zwangere vrouw tegenover een dergelijk middel als fibrinogeenconcentraat staat. Dit geldt met name in het geval van een verhoogd risico op HPP.
Gezien de kleine kans op bijwerkingen en overlap hiervan met andere bloedproducten en stollingsfactor concentraten, de (zeldzame) indicaties waarbij fibrinogeenconcentraat wordt toegediend en de klinische setting van acute HPP met reeds lopende intraveneuze therapie is de verwachte belasting voor de patiënt in alle andere gevallen als minimaal te beschouwen.
Kosten (middelenbeslag)
De kosten van fibrinogeenconcentraat zijn hoog, zo’n ca. 500 EUR euro per flacon van 1 gram. Kosten-baten analyses zijn niet uitgevoerd voor fibrinogeen in de setting van HPP. Aangezien er geen wetenschappelijk bewijs is dat vroege suppletie van fibrinogeen bij HPP klinische uitkomsten verbetert, is in deze setting geen kosteneffectiviteit te verwachten. Bij gerichte behandeling o.b.v. een vastgesteld fibrinogeentekort m.b.v. point-of-care of standaard bloedstollingsonderzoek is dit mogelijk wel het geval, maar onderzoek is bij de werkgroep niet bekend.
Aanvaardbaarheid, haalbaarheid en implementatie
Er is geen wetenschappelijk bewijs dat vroege suppletie van fibrinogeen bij HPP klinische uitkomsten verbetert. Daarmee staat de aanvaardbaarheid van een dergelijke interventie sterk ter discussie en is haalbaarheid en implementatie minder relevant. Fibrinogeenconcentraat is mogelijk niet overal (snel) beschikbaar.
Rationale van aanbeveling-1: weging van argumenten voor en tegen de interventies
Er is enig bewijs dat toediening van fibrinogeen bij vrouwen met bloedverlies postpartum van ten minste 500 mL na vaginale bevalling of keizersnede weinig tot géén effect heeft op extra bloedverlies, in vergelijking met placebo of geen toediening van fibrinogeen. Er is geen wetenschappelijk bewijs dat vroege suppletie van fibrinogeen bij HPP vanaf 500 mL klinische uitkomsten verbetert.
De huidige literatuur geeft aanwijzingen dat profylactische toediening van fibrinogeen medisch en kostentechnisch géén voordelen biedt t.o.v. de standaard behandeling bij HPP. De bewijslast voor deze aanbeveling berust op 3 RCTs, die deels onvoldoende gepowered waren om een duidelijk effect waar te nemen (low Grade).
Rationale van aanbeveling-2: weging van argumenten voor en tegen de interventie
In de klinische setting van aanhoudende HPP > 1.5L kan overwogen worden fibrinogeenconcentraat toe te dienen bij een aangetoond fibrinogeen tekort m.b.v. Clauss fibrinogeen test (fibrinogeen <2g/L) of FIBTEM A5. Wanneer in de acute situatie van massaal ongecontroleerd bloedverlies met klinische verdenking op acute coagulopathie en de noodzaak tot het opstarten van een massaal transfusieprotocol danwel in de situatie van een abruptio placentae of vruchtwaterembolie kan empirisch toedienen van fibrinogeenconcentraat (bijv. 4 gram iv.) worden overwogen, ook als er nog geen stollingstest uitslagen beschikbaar zijn (expert opinion).
In de setting van aanhoudende HPP zijn het kleine volume, de veiligheid, gestandaardiseerde doseringen en de snelle beschikbaarheid van fibrinogeenconcentraat voordelen t.o.v. andere stollingsfactor producten en plasma. Een fibrinogeenwaarde >2 g/L lijkt adequaat voor hemostase tijdens HPP. Wanneer een verlaagd fibrinogeen <2g/L is vastgesteld tijdens HPP, heeft fibrinogeenconcentraat de voorkeur boven plasma toediening (expert opinion).
Zie module: stollingscorrectie bij HPP voor de FIBTEM A5 afkapwaarde bij gebruik van TEG/ROTEM
Onderbouwing
Achtergrond
In healthy women a natural increase in procoagulant factors and a decrease in anticoagulant factors occur during pregnancy, peaking around childbirth. This shift to a procoagulant state provides natural protection against excessive blood loss during delivery. Fibrinogen—the end product of the coagulation cascade—also rises during pregnancy to approximately 4-6 g/L (Uchikova 2005, Huq 2012). Under normal circumstances, fibrinogen is the clotting factor with the highest concentration in blood. Blood clot strengthening is dependent on fibrinogen concentration. During acute bleeding, fibrinogen levels are the first to drop because fibrinogen polymerization is irreversible. A low fibrinogen level (<2 g/L) is highly predictive of progression to severe postpartum haemorrhage (PPH) (de Lloyd 2011, Hofer 2023). Intravenous fibrinogen supplementation is therefore a potential intervention to prevent progression to severe PPH.
Studies to date indicate that the use of fibrinogen in the context of PPH is safe, readily available, and volume-sparing compared to plasma transfusion and cryoprecipitate. (Vermeulen 2022) However, the role of early fibrinogen supplementation in terms of effectiveness and cost-efficiency in the treatment of PPH in secondary and tertiary care settings remains unclear. The question is whether fibrinogen should be administered immediately in cases of persistent bleeding or only to women with confirmed hypofibrinogenemia. Treatment with fibrinogen concentrate is expensive and may not be readily available in all locations. Currently, there is (likely) variation in practice in secondary and tertiary care regarding the use of fibrinogen in PPH. The key question is whether early fibrinogen supplementation is beneficial (and cost-effective) when administered early in cases of persistent postpartum bleeding and whether its administration should be based on actual fibrinogen levels.
Conclusies / Summary of Findings
|
Low GRADE |
In women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section, administration of fibrinogen may result in little or no effect on additional blood loss as compared to placebo or no administration of fibrinogen. Source: Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on hysterectomy when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on maternal death when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Zaidi (2020), Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on blood transfusion when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Zaidi (2020), Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on use of additional haemostatic intervention when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Zaidi (2020), Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on transfer to higher level of care when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Zaidi (2020), Ducloy-Bouthors (2021) |
|
Very low GRADE |
The evidence is very uncertain about the effect of fibrinogen on adverse effects when compared with placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section. Source: Zaidi (2020), Ducloy-Bouthors (2021) |
|
No GRADE |
No evidence was found regarding the chance of , shock, coagulopathy, organ dysfunction, women's sense of wellbeing, acceptability, satisfaction with the intervention and breastfeeding in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section, who were administered fibrinogen compared to placebo or no fibrinogen. Source: None |
Samenvatting literatuur
Description of studies
Zaidi (2020) wrote a systematic review focusing on early fibrinogen replacement therapy in severe postpartum haemorrhage (PPH). CDSR & CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed (for electronic publications ahead of print only), Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index- Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal (ICTRP) were searched from inception to June 2019. Studies were included if they included pregnant women of any age, >24 weeks gestation with PPH defined as estimated blood loss ≥500 mL up to 24 hours postdelivery. If in a study fibrinogen was compared with another hemostatic intervention, it was excluded. Initially, 14 studies were selected based on title and abstract. A total of 5 studies (2 completed RCTs and 3 ongoing trials) were included in this systematic review. A meta-analysis was not possible because only 2 RCTs were completed and these were not sufficiently homogenous. Zaidi (2020) rated risk of bias for one RCT as low and they rated another RCT unclear.
Ducloy-Bouthors (2021) performed a multicentre, double-blind, randomized placebo-controlled trial to assess the efficacy and safety of early fibrinogen concentrate supplementation in PPH following vaginal delivery. In total, 437 patients were included of which 224 received fibrinogen and 213 received placebo. Inclusion criteria were: age ≥18 years, with PPH, i.e. vaginal bleeding ≥500 mL, following vaginal delivery requiring continuous intravenous prostaglandin administration (sulprostone, at an initial rate of 500 mcg/h, according to guidelines), with at least one haemoglobin (Hb) value available for the third trimester of pregnancy. The other inclusion and non-inclusion criteria were described previously by Ducloy-Bouthors (2016). A 1:1 ratio randomization was stratified per centre with a block size of 4. From April 2014 to August 2018, 443 patients were randomized and 437 retained in the intention-to-treat population; 244 patients received 3 g [8.82 mcmol] fibrinogen concentrate and 213 patients received placebo. Failure was the composite primary efficacy endpoint: at least 4 g/dl of haemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following fibrinogen or placebo administration. The RCT was funded by a company that holds marketing authorization for Clottafact (fibrinogen concentrate), however there are no specific reasons to expect risk of bias.
Results
Blood loss (critical)
Ducloy-Bouthors (2021) reported as secondary outcome additional blood loss from time of fibrinogen or placebo administration to day 2 (mean ± SD) of 304.7 ± 386.2 ml in the fibrinogen group and 319.7 ± 417.1 ml in the placebo group. This resulted in a standardized mean difference of -0.04 [95% CI -0.23 to 0.15]. The mean total blood loss in the fibrinogen and placebo groups was 1555 and 1723 ml, respectively (p=0.21).
Shock (critical)
None of the studies described this outcome measure.
Coagulopathy (important)
None of the studies described this outcome measure.
Hysterectomy (important)
Ducloy-Bouthors (2021) reported 1 (0.5%) case of hysterectomy in the placebo group and no hysterectomy in the fibrinogen group. This resulted in a risk ratio of 0.32 [95% CI 0.01 to 7.77].
Organ dysfunction (critical)
Ducloy-Bouthors (2021) reported that organ failure was rare; two patients in each group had a Sequential Organ Failure Assessment (SOFA) score ≥ 3. This resulted in a risk ratio of 0.95 [95% CI 0.14 to 6.71].
Maternal death (critical)
Zaidi (2020) reported no deaths relating to PPH in either study up to 30 days, however in one RCT 5/53 participants were lost to follow-up.
Ducloy-Bouthors (2021) also reported no maternal deaths in both groups.
Blood transfusion (critical)
Zaidi (2020) reported that based on the two completed studies there was no evidence of a difference in the need for a red blood cell transfusion between participants who received fibrinogen and those that did not (risk ratio 0.83 [95% CI 0.54 to 1.26]).
Ducloy-Bouthors (2021) reported RBC transfusion of ≥ 2 units from time of fibrinogen or placebo administration to day 2 in 51 women in the fibrinogen group and in 52 women in the placebo group. This resulted in a risk ratio of 0.94 [95% CI 0.67 to 1.31].
Use of additional haemostatic intervention (important)
Ducloy-Bouthors (2021) reported 8 (3.6%) cases of at least one invasive haemostatic intervention (including arterial embolization, arterial ligation or hysterectomy) in the fibrinogen group and 10 (4.8%) cases in the placebo group. This resulted in a risk ratio of 0.76 [95% CI 0.31 to 1.90]. Intra-uterine balloon was reported in 63 (28.6%) patients in the fibrinogen group and in 61 (29.0%) in the placebo group, resulting in a risk ratio of 0.99 [95% CI 0.73 to 1.33]. At least one rescue procedure was reported in 65 (29.5%) patients in the fibrinogen group and in 64 (30.5%) in the placebo group, resulting in a risk ratio of 0.97 [95% CI 0.73 to 1.29].
Zaidi (2020) reported no (non-surgical) hemostatic interventions in the fibrinogen or control groups in the two RCTs. Additionally, surgical intervention until discharge, defined as any physical intervention including but not limited to intra-uterine balloon tamponade, uterine arterial ligation/embolization, internal iliac artery ligation, brace uterine sutures, laparotomy or any physical intervention to achieve hemostasis) was reported in only one RCT. This was reported in 5 (17.9%) patients in the fibrinogen group and in 5 (18.5%) patients in the control group in one RCT, resulting in a risk ratio of 0.96 [95% CI 0.31 to 2.96]. This outcome was not reported in the other RCT.
Transfer to higher level of care (important)
Ducloy-Bouthors (2021) reported 62 (28.2%) cases of intensive care or resuscitation in the fibrinogen group and 54 (25.7%) cases in the placebo group. This resulted in a risk ratio of 1.10 [95% CI 0.80 to 1.50].
Zaidi (2020) reported that in both RCTs no transfers to another hospital with additional facilities for management of ongoing bleeding were observed. Additionally, admission to level 3 care was reported in only one RCT. This was reported in 2 (7.1%) patients in the fibrinogen group and in 2 (7.4%) patients in the control group in one RCT, resulting in a risk ratio of 0.96 [95% CI 0.15 to 6.37]. This outcome was not reported in the other RCT.
Women's sense of wellbeing (important)
None of the studies described this outcome measure.
Acceptability (important)
None of the studies described this outcome measure.
Satisfaction with the intervention (important)
None of the studies described this outcome measure.
Breastfeeding (important)
None of the studies described this outcome measure.
Adverse effects (important)
Ducloy-Bouthors (2021) reported that 94 (42.9%) adverse effects were recorded in the fibrinogen group and 106 (49.8%) in the placebo group, resulting in a risk ratio of 0.84 [95% CI 0.69 to 1.03], favouring fibrinogen.
Zaidi (2020) reported no results for adverse effects, only that in 148 participants in one RCT data on adverse events was missing.
Level of evidence of the literature
According to GRADE, systematic reviews of randomized controlled trials (RCTs) and RCTs start at a high level of evidence.
The level of evidence regarding the outcome measure blood loss was downgraded to low GRADE. Downgraded by one level for risk of bias and one level for imprecision (small sample size and reported in only one study).
As none of the studies selected for the summary of literature focused on shock, no GRADE conclusions could be drawn.
As none of the studies selected for the summary of literature focused on coagulopathy, no GRADE conclusions could be drawn.
The GRADE level of evidence regarding the outcome measure hysterectomy was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (only one study and very low number of events).
As none of the studies selected for the summary of literature focused on organ dysfunction, no GRADE conclusions could be drawn.
The GRADE level of evidence regarding the outcome measure maternal death was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (no events in either arm and low number of patients).
The GRADE level of evidence regarding the outcome measure blood transfusion was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (confidence interval includes both clinically significant borders).
The GRADE level of evidence regarding the outcome measure use of additional haemostatic intervention was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (confidence interval includes both clinically significant borders).
The GRADE level of evidence regarding the outcome measure transfer to higher level of care was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (confidence interval includes both clinically significant borders).
As none of the studies selected for the summary of literature focused on women’s sense of wellbeing, no GRADE conclusions could be drawn.
As none of the studies selected for the summary of literature focused on acceptability, no GRADE conclusions could be drawn.
As none of the studies selected for the summary of literature focused on satisfaction with the intervention, no GRADE conclusions could be drawn.
As none of the studies selected for the summary of literature focused on breastfeeding, no GRADE conclusions could be drawn.
The GRADE level of evidence regarding the outcome measure adverse effects was downgraded to very low GRADE: downgraded by one level for indirectness (most patients in the SR had severe PPH (>1000 mL blood loss)) and two for imprecision (confidence interval includes both clinically significant borders).
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question: What are the (un)favourable effects of fibrinogen compared to placebo or no fibrinogen in women with postpartum blood loss of at least 500 mL after vaginal birth or cesarean section?
| P: | postpartum women with ongoing blood loss of more than 500 mL after vaginal birth or cesarean section |
| I: | treatment with fibrinogen |
| C: | placebo or no treatment with fibrinogen |
| O: | blood loss, shock, coagulopathy, hysterectomy, organ dysfunction, maternal death, blood transfusion, use of additional hemostatic intervention, transfer for higher level of care, women's sense of wellbeing, acceptability, satisfaction with the intervention, breastfeeding, adverse effects. |
Relevant outcome measures
The working group considered blood loss more than 1000 mL (dichotomous) , hysterectomy shock, organ dysfunction, transfer for higher level of care, maternal death and blood transfusion as critical outcome measures for decision making; and blood loss (continuous outcome measure), coagulopathy, use of additional hemostatic intervention, women's sense of wellbeing, acceptability, satisfaction with the intervention, breastfeeding, adverse effects as important outcome measures for decision making.
A priori, the working group used definitions for the outcome measures listed above as described in the international Delphi consensus study by Meher (2018).
The working group defined a 1% difference for maternal death (RR < 0.99 or > 1.01) and 10% (RR < 0.90 or > 1.10) for other critical outcome measures as a minimal clinically (patient) important difference. For the other outcomes, a 25% difference for dichotomous outcomes (RR < 0.8 or > 1.25) and 0.5 SD for continuous outcomes was taken as minimal clinically (patient) important difference. It is agreed that blood loss >1000 mL becomes clinically relevant.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 6 November 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 328 hits. Studies were selected based on the following criteria: systematic reviews, randomized controlled trials and observational (case-control and cohort) studies comparing treatment with fibrinogen with no treatment with fibrinogen or placebo in postpartum women with blood loss of >500 mL after vaginal birth or cesarean section. Five studies were initially selected based on title and abstract screening. After reading the full text, three studies were excluded (see the table with reasons for exclusion under the tab Methods), and two studies were included.
Results
Two studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.
Referenties
- Bell SF, de Lloyd L, Preston N, Collins PW. Managing the coagulopathy of postpartum haemorrhage: an evolving role for viscoelastic hemostatic assays. J Thromb Haemost. 2023 Aug;21(8):2064-2077. doi: 10.1016/j.jtha.2023.03.029. Epub 2023 Apr 3. PMID: 37019365.
- Caram-Deelder C, McKinnon Edwards H, Zdanowicz JA, van den Akker T, Birkegård C, Blatný J, van der Bom JG, Colucci G, van Duuren D, van Geloven N, Henriquez DDCA, Knight M, Korsholm L, Landorph A, Lavigne Lissalde G, McQuilten ZK, Surbek D, Wellard C, Wood EM, Mercier FJ. Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Haemorrhage. J Clin Med. 2024 May 1;13(9):2656. doi: 10.3390/jcm13092656. PMID: 38731185; PMCID: PMC11084845.
- de Lloyd L, Bovington R, Kaye A, Collis RE, Rayment R, Sanders J, Rees A, Collins PW. Standard haemostatic tests following major obstetric haemorrhage. Int J Obstet Anesth. 2011 Apr;20(2):135-41. doi: 10.1016/j.ijoa.2010.12.002. PMID: 21439811.
- Ducloy-Bouthors AS, Mercier FJ, Grouin JM, Bayoumeu F, Corouge J, Le Gouez A, Rackelboom T, Broisin F, Vial F, Luzi A, Capronnier O, Huissoud C, Mignon A; FIDEL working group. Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial. BJOG. 2021 Oct;128(11):1814-1823. doi: 10.1111/1471-0528.16699. Epub 2021 Apr 7. PMID: 33713384.
- Ducloy-Bouthors AS, Mignon A, Huissoud C, Grouin JM, Mercier FJ. Fibrinogen concentrate as a treatment for postpartum haemorrhage-induced coagulopathy: A study protocol for a randomised multicentre controlled trial. The fibrinogen in haemorrhage of DELivery (FIDEL) trial. Anaesth Crit Care Pain Med. 2016 Aug;35(4):293-8. doi: 10.1016/j.accpm.2015.10.011. Epub 2016 Mar 19. PMID: 27004917.
- Hofer S, Blaha J, Collins PW, Ducloy-Bouthors AS, Guasch E, Labate F, Lança F, Nyfløt LT, Steiner K, Van de Velde M. Haemostatic support in postpartum haemorrhage: A review of the literature and expert opinion. Eur J Anaesthesiol. 2023 Jan 1;40(1):29-38. doi: 10.1097/EJA.0000000000001744. Epub 2022 Sep 22. PMID: 36131564; PMCID: PMC9794135.
- Hugon-Rodin J, Carrière C, Claeyssens S, Trillot N, Drillaud N, Biron-Andreani C, Lavenu-Bombled C, Wieland A, Flaujac C, Stieltjes N, Lebreton A, Brungs T, Hegglin A, Fiore M, Desconclois C, Gay V, Tardy-Poncet B, Beurrier P, Barbay V, Chamouni P, Maistre E, Simurda T, Casini A. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J Thromb Haemost. 2023 Aug;21(8):2126-2136. doi: 10.1016/j.jtha.2023.04.035. Epub 2023 May 11. PMID: 37172732.
- Huq FY, Kulkarni A, Agbim EC, Riddell A, Tuddenham E, Kadir RA. Changes in the levels of factor VIII and von Willebrand factor in the puerperium. Haemophilia. 2012 Mar;18(2):241-5. doi: 10.1111/j.1365-2516.2011.02625.x. Epub 2011 Sep 28. PMID: 21951573.
- Meher S, Cuthbert A, Kirkham JJ, Williamson P, Abalos E, Aflaifel N, Bhutta ZA, Bishop A, Blum J, Collins P, Devane D, Ducloy-Bouthors AS, Fawole B, Gülmezoglu AM, Gutteridge K, Gyte G, Homer C, Mallaiah S, Smith JM, Weeks AD, Alfirevic Z. Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study. BJOG. 2019 Jan;126(1):83-93. doi: 10.1111/1471-0528.15335. Epub 2018 Jul 29. PMID: 29920912.
- Uchikova EH, Ledjev II. Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Reprod Biol. 2005 Apr 1;119(2):185-8. doi: 10.1016/j.ejogrb.2004.06.038. PMID: 15808377.
- Zaidi A, Kohli R, Daru J, Estcourt L, Khan KS, Thangaratinam S, Green L. Early Use of Fibrinogen Replacement Therapy in Postpartum Haemorrhage-A Systematic Review. Transfus Med Rev. 2020 Apr;34(2):101-107. doi: 10.1016/j.tmrv.2019.12.002. Epub 2020 Jan 28. PMID: 32037228.
Evidence tabellen
Evidence table for systematic review of RCT's and observational studies (intervention studies)
Research question: What are the (un)favorable effects of fibrinogen compared to placebo or no fibrinogen in women with postpartum blood loss of at least 500 ml after vaginal birth or cesarean section?
|
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison / control (C)
|
Follow-up |
Outcome measures and effect size |
Comments |
|
Zaidi, 2020 |
SR of RCTs
Literature search from inception to June 2019
A: Wikkelso, 2015 B: Collins, 2017
Study design: A: RCT B: RCT
Setting and Country: A: Denmark B: UK
Source of funding and conflicts of interest: The SR was funded by Barts Charity. The funders had no role in the study design, data collection/analysis or preparation of this article. The views expressed in this article are those of the authors and not necessarily of the funders |
Inclusion criteria SR: Studies were included if they were RCTs (including cluster-RCTs with at least two intervention sites in each arm), non-randomized trials, repeated measures studies, interrupted time series studies and controlled before-and-after studies where fibrinogen replacement therapy was administered in the context of PPH. There is no universally accepted definition for PPH, however the most widely used definition is blood loss of at least 500 mL within 24 hours of delivery [7, 16]. Hence for this review, studies were eligible if they included pregnant women of any age, at greater than 24 weeks gestation who had a diagnosis of PPH defined as estimated blood loss ≥500 mL up to 24 hours postdelivery.
Exclusion criteria SR: We excluded studies that compared fibrinogen replacement therapy with another hemostatic intervention, e.g. early fibrinogen replacement + standard of care versus tranexamic acid + standard of care or any other hemostatic agent that was not fibrinogen replacement therapy.
2 completed RCTs included (and 3 ongoing studies, without results)
Important patient characteristics at baseline: 299 patients in 2 RCTs
N, mean age A: 244 patients B: 55 patients
Sex: A: 100% female B: 100% female
|
Describe intervention:
A: Fibrinogen Concentrate, 2g B: Fibrinogen Concentrate,1g Guided by viscoelastic testing
|
Describe control:
A: 100 mL Normal Saline B: 50 mL Normal Saline
|
End-point of follow-up:
A:
B:
For how many participants were no complete outcome data available? (intervention/control) A: unknown B: 5/53 participants were lost to follow-up
|
Outcome measure-1 Defined as the need for allogeneic blood transfusion at 24 hours, but different between the two RCTs: A: Need for RBC transfusion <6 weeks post PPH B: Total number of allogeneic blood products up to point of hospital discharge
Effect measure: RR, RD, mean difference [95% CI]: A: Intervention n=25, (20.3%) Control n=26 (21.5%) B: Mean transfusion Rate: Intervention: 2.07 Control: 2.78
Pooled effect: risk ratio 0.83 [95% CI 0.54 to 1.26] favoring fibrinogen
Heterogeneity (I2):
Outcome measure-2 ....
Outcome measure-3 ....
|
Risk of bias (high, some concerns or low): Tool used by authors: Cochrane Risk of bias tool
A: low risk of bias B: unclear
Facultative:
Brief description of author’s conclusion This review has demonstrated the paucity of evidence on the early use of fibrinogen replacement therapies in postpartum hemorrhage. The small sample size of included studies and their heterogeneity warrants us to interpret these results with extreme caution until further evidence become available.
Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question
Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading
All-cause mortality Very low GRADE. Downgraded by 1 for lack of generalizability. Only participants with severe PPH were included in the studies. Downgraded by 2 for imprecision (no events in either arm, rare event)
Blood transfusion Low GRADE. The GRADE level of evidence was downgraded by two, one for imprecision (wide confidence intervals that include clinically significant benefit as well as no effect) and one for generalizability (only patients with severe post-partum hemorrhage were included in either study
Sensitivity analyses (excluding small studies; excluding studies with short follow-up; excluding low quality studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question
Heterogeneity: clinical and statistical heterogeneity; explained versus unexplained (subgroupanalysis) |
Evidence table for intervention studies (RCT's and observational studies)
Research question: What are the (un)favorable effects of fibrinogen compared to placebo or no fibrinogen in women with postpartum blood loss of at least 500 ml after vaginal birth or cesarean section?
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Ducloy-Bouthors, 2021 |
Type of study: Multicentre, double-blind, randomised placebo-controlled trial
Setting and country: 30 French hospitals
Funding and conflicts of interest: The study was sponsored and funded by LFB (Les Ulis, France) (Appendix S2), which holds the marketing authorisation for Clottafact(fibrinogen concentrate). The study was conceived and performed according to a double-blind versus placebo design. Conception conduct of the study, quality assessment, data management, blinded data validation, statistical management quality and writing of the paper were conducted under the oversight of the scientific committee. The awarded grant included external peer review for data collection, applicable regulation and scientific quality.
Disclosure of interests ASD-B, FJM, AM, CH and JMG received fees from LFB as members of the FIDEL trial Scientific Committee. FJM also received fees from LFB for symposium lectures. FBr and FV received fees from LFB as FIDEL investigators. ALG, FV and FBa received fees from LFB for dispensing medical training. FBr and AL were invited by LFB to a congress. TB received fees from LFB for a work of expert. OC reports grants from LFB as an Euraxi Pharma employee. The other authors of the present manuscript do not declare any disclosures of interest. |
Inclusion criteria: (age ≥18 years, with PPH, i.e. vaginal bleeding ≥500 ml) following vaginal delivery requiring continuous intravenous prostaglandin administration (sulprostone, at an initial rate of 500 mcg/h, according to guidelines16), with at least one haemoglobin (Hb) value available for the third trimester of pregnancy)
Exclusion criteria:
N total at baseline: Intervention: 224 Control: 213
Important prognostic factors2: For example age ± SD: I: 30.5 ± 5.6 C: 30.3 ±5.4
Sex: I: 100% female C: 100% female
Groups comparable at baseline? Yes |
Describe intervention (treatment/procedure/test):
Investigational medicinal product (IMP 3 g [8.82 mcmol] fibrinogen concentrate)
Each vial of fibrinogen concentrate (1.5 g) and placebo was reconstituted in 100 ml of sterile water and administered at a flow rate ≤20 ml/min within 30 minutes following the start of the sulprostone infusion.
|
Describe control (treatment/procedure/test):
Investigational medicinal product (IMP 3 g placebo) |
Length of follow-up: 6 ± 2 weeks
Loss-to-follow-up: Intervention: 4 (1.8%) Reasons (describe) missing primary endpoints
Control: 3 (1.4%) Reasons (describe) missing primary endpoints
Incomplete outcome data: Intervention: N (%) Reasons (describe)
Control: N (%) Reasons (describe)
|
Outcome measures and effect size (include 95%CI and p-value if available):
Composite failure, defined as a patient having lost at least 4 g/dl of Hb compared with the reference Hb level within the 48 hours following investigational medicinal product (IMP) administration;, and/or requiring transfusion of at least two units of packed RBCs within 48 hours following the administration of the IMP: OR: 0.99 (95% CI 0.66 to 1.47)
RBC transfusion ≥2 Units from H0 to D2: OR: 1.00 (95% CI 0.63 to 1.60)
Hb loss ≥4 g/dl from reference level to D2: OR: 1.02 (95% CI 0.62 to 1.67)
|
Primary outcome is a composite failure score, other outcomes of interest for the working group are described as secondary outcomes |
Risk of bias tables
Risk of bias table for intervention studies (randomized controlled trials)
Research question: What are the (un)favorable effects of fibrinogen compared to placebo or no fibrinogen in women with postpartum blood loss of at least 500 ml after vaginal birth or cesarean section?
|
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented?
Were patients blinded?
Were healthcare providers blinded?
Were data collectors blinded?
Were outcome assessors blinded?
Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
|
Ducloy-Bouthors, 2021 |
Definitely yes;
Reason: Randomisation was stratified per centre with a block size of 4; IMP containers were sequentially numbered according to the computer-generated randomisation sequence. |
Probably yes;
Reason: Reconstitution of fibrinogen and formulation of the placebo (two vials = 3 g of fibrinogen or placebo per patient) were carried out by trained research personnel not involved in the patients’ care. |
Probably yes;
Reason: Blinding of care providers and patients was maintained throughout using a masking system and tinted tubing. (blinding of data collectors and analysts not reported) |
Probably no;
Reason: 3 missing primary endpoints. No imputation methods were used. |
Probably no;
Reason: Many relevant outcomes were reported, but (collection of) secondary outcomes were not well described (a priori) in methods |
Probably no;
Reason: The study was sponsored and funded by the company LFB (Les Ulis, France), which holds the marketing authorisation for Clottafact(fibrinogen concentrate). Authors also individually received fees from LFB for symposium lectures, congress participation, Euraxi Pharma employee. However: results are not in favour of the company.
The study was sponsored and funded by LFB (Les Ulis, France) (Appendix S2), which holds the marketing authorisation for Clottafact_ (fibrinogen concentrate). The study was conceived and performed according to a double-blind versus placebo design. Conception conduct of the study, quality assessment, data management, blinded data validation, statistical management quality and writing of the paper were conducted under the oversight of the scientific committee. The awarded grant included external peer review for data collection, applicable regulation and scientific quality.
Disclosure of interests ASD-B, FJM, AM, CH and JMG received fees from LFB as members of the FIDEL trial Scientific Committee. FJM also received fees from LFB for symposium lectures. FBr and FV received fees from LFB as FIDEL investigators. ALG, FV and FBa received fees from LFB for dispensing medical training. FBr and AL were invited by LFB to a congress. TB received fees from LFB for a work of expert. OC reports grants from LFB as an Euraxi Pharma employee. The other authors of the present manuscript do not declare any disclosures of interest.
Acknowledgements The sponsor (LFB, Les Ulis, France) supervised the logistics and funding of the trial, provided the IMPs and approved the decision to submit the manuscript for publication. … The contract research organisation Euraxi Pharma (Jou_e-l_es- Tours, France) was appointed by the sponsor to coordinate the study. |
Some concerns |
Table of excludes studies
|
Reference |
Reason for exclusion |
|
Deleu F, Deneux-Tharaux C, Chiesa-Dubruille C, Seco A, Bonnet MP; EPIMOMS study Group. Fibrinogen concentrate and maternal outcomes in severe postpartum hemorrhage: A population-based cohort study with a propensity score-matched analysis. J Clin Anesth. 2022 Oct;81:110874. doi: 10.1016/j.jclinane.2022.110874. Epub 2022 Jun 2. PMID: 35662057. |
Observational study that focuses on outcomes that were not defined as in our core set of outcomes. This study combines death and near-miss in one outcome measure, which makes it impossible to dissect the crucial outcome of maternal death |
|
Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, Weeks AD, Sanders J, Aawar N, Townson J, Hood K, Hall JE, Collis RE. Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. Br J Anaesth. 2017 Sep 1;119(3):411-421. doi: 10.1093/bja/aex181. PMID: 28969312. |
Randomized controlled trial that is included in the systematic literature review by Zaidi (2020) |
|
Wikkelsø AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, Pedersen LM, Troelstrup A, Lauenborg J, Mitchell AU, Fuhrmann L, Svare J, Madsen MG, Bødker B, Møller AM; FIB-PPH trial group. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth. 2015 Apr;114(4):623-33. doi: 10.1093/bja/aeu444. Epub 2015 Jan 13. PMID: 25586727. |
Randomized controlled trial that is included in the systematic literature review by Zaidi (2020) |
Verantwoording
Beoordelingsdatum en geldigheid
Publicatiedatum : 12-12-2025
Beoordeeld op geldigheid : 12-12-2025
Algemene gegevens
De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd door de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.
Samenstelling werkgroep
Voor het ontwikkelen van de richtlijnmodule is in 2022 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten met haemorrhagia postpartum.
Werkgroep
- Dr. M.(Martina) Porath (voorzitter) (NVOG)
- Dr. H.C.J. (Liesbeth) Scheepers (NVOG)
- Dr. D.D.C.A. (Dacia) Henriquez (NVOG)
- Dr. J.M. (Annemieke) Middeldorp(NVOG)
- Prof. dr. T.H. (Thomas) van den Akker (NVOG)
- Dr. P. (Paul) Ramler (NVOG) (tot September 2023)
- Dr. K.P.M. (Karin) van Galen(NIV)
- Drs. H.W. (Hannah) de Klerk (KNOV)
- Drs. L. (Lianne) Zondag (KNOV)
- Prof. dr. ir. Y.M.C. (Yvonne) Henskens (NVKC)
- Dr. I.C.M. (Ingrid) Beenakkers (NVA)
- Dr. S. (Simone) Willems (NVA)
- Mw. I. (Ilse) van Ee (PFN)
Klankboardgroep
- Drs. K. (Klaartje) Caminada (AZN)
- Mw. B. (Britt) Ketelaars (PFN)
Met ondersteuning van
- Dr. M. (Mohammadreza) Abdollahi, adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Dr. I.M. (Irina) Mostovaya, senior adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Dr. J. (Jana) Tuijtelaars, adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Drs. D.A.M. (Danique) Middelhuis, adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Dr. M. (Majke) van Bommel, adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Dr. L. (Leanne) Küpers, adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Drs. D.A.M. (Fieke) Pepping, junior adviseur, Kennisinstituut van de Federatie van Medisch Specialisten
- Linda Niesink, medisch informatie specialist, Kennisinstituut van de Federatie Medisch Specialisten
- Laura Boerboom, medisch informatie specialist, Kennisinstituut van de Federatie Medisch Specialisten
- Alies Oost, medisch informatie specialist, Kennisinstituut van de Federatie Medisch Specialisten
Belangenverklaringen
Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.
|
Naam |
Hoofdfunctie |
Nevenwerkzaamheden |
Persoonlijke financiële belangen |
Persoonlijke relaties |
Extern gefinancierd onderzoek |
Intellectuele belangen en reputatie |
Overige belangen |
Datum |
Restrictie |
|
Martina Porath |
gynaecoloog-perinatoloog Maxima Medisch Centrum |
Voorzitter focusgroep Acute Verloskunde Noord-Brabant Lid NVOG werkgroep Otterlo |
geen |
geen |
geen |
geen |
geen |
04/28/2025 |
|
|
Liesbeth Scheepers |
perinatoloog MUMC |
Richtlijnen commissie Otterloo groep Voorzitter Regioconsortium Geboortezorg Limburg Vice voorzitter Perinatale audit Limburg |
Geen |
Nee |
ZONMW onderzoek, niet op dit onderwerp |
Nee |
Nee |
04/25/2025 |
|
|
Annemieke Middeldorp |
Gynaecoloog Perinatoloog Leids Universitair Medisch Centrum, gestopt met werken vanaf 2024 |
geen |
geen |
geen |
geen |
geen |
geen |
04/25/2025 |
|
|
Dacia Henriquez |
Gynaecoloog, Perinatoloog, Amphia Ziekenhuis |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
04/28/2025 |
|
|
Thomas van den Akker |
Gynaecoloog perinatoloog, LUMC, hoogleraar Verloskunde |
Hoogleraar VU *Global Maternal Health, Athena Instituut. *Perined bestuurslid *RvT Wemos. *FMG Pijlervoorzitter NVOG *Vz working party for international safe motherhood and reproductive health. *Perinatale audit regiovoorzitter. Alles onbetaald. |
Geen |
Geen |
Geen |
Door werk van de commissie komt het werk van mijn voormalig promovendi Ada Gillissen en Paul Ramler meer in de aandacht staan, omdat sommige aanbevelingen hierop gebaseerd zijn (met name van laatstgenoemde ten aanzien van ballon versus embolisatie).
Het feit dat ik als bijdrager op de richtlijn sta kan gezien worden als ten goede komend aan de boegbeeldfunctie die ik bij de NVOG heb, maar het effect hiervan lijkt beperkt in het licht van mijn andere activiteiten. |
Geen |
04/25/2025 |
|
|
Paul Ramler (tot September 2023) |
AIOS Gynaecologie, cluster Leiden |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
29/01/2023 |
|
|
Ingrid Beenakkers |
Anesthesioloog, UMCU/WKZ |
geen |
geen |
geen |
geen |
geen |
geen |
04/28/2025 |
|
|
Simone Anna Alexandra Sijm-Willems |
Anesthesioloog Radboudumc |
- |
-zs |
- |
- |
- |
- |
04/25/2025 |
|
|
Karin van Galen |
internist-hematoloog UMC Utrecht |
geen |
geen |
n.v.t. |
Octapharma: Pregnancy and inherited bleeding disorders - unresticted research grant, projectleider. |
Voorzitter Nederlands Zorgnetwerk Vrouwen met een stollingsstoornis. Tot Febr 2025 voorzitter Women and Girls with beleeding Disorders Group European Assosiation for Heamophilia and Alied Disorders - momenteel nog actief lid van deze werkgroep. |
n.v.t. |
04/25/2025 |
|
|
Yvonne Henskens |
Klinisch chemicus, waarnemend hoofd Centraal Diagnostisch Laboratorium Hoogleraar Klinische Chemie ihb Hemostase |
Voorzitter Vereniging Hematologisch Laboratoria 2020-heden Lid Vici beoordelingscie 2022 Lid raad van Advies NVKC 2023-heden Adviseur Promicol 2020-heden |
geen |
geen |
Voor alle studies in het kader van mijn leerstoel worden reagentia of apparatuur gratis of met korting verkregen, hierbij wordt geen enkele IVD methode of bedrijf uitgesloten mits het past in het doel van mijn leerstoel. Noyons stipendium NVKC (prijs) Stago / Validatie van apparatuur en/of reagentia / Ja Siemens / Validatie van apparatuur en/of reagentia / Ja Werfen / Validatie van apparatuur en/of reagentia / N Nodia / Validatie van apparatuur en/of reagentia / Nee Promicol / Validatie van apparatuur en/of reagentia / Nee |
nee |
nee |
04/25/2025 |
|
|
Hannah de Klerk |
Zelfstandig eerstelijns verloskundige (ZZP), betaald PhD aanstelling Amsterdam UMC, locatie VUMc, onbetaald |
Gastdocent HU, betaald Projectleider KNOV, betaald |
geen |
nee |
nee |
nee |
nee |
7/10/2022 |
|
|
Lianne Zondag |
Eerstelijns verloskundige - verloskundige praktijk de Toekomst - Geldermalsen KNOV - senior richtlijnonwikkelaar |
Bestuurslid Netwerk Geboortezorg Rivierenland PhD candidate Maastricht University |
Geen |
Geen |
Geen |
Geen |
Geen |
2/6/2023 |
|
|
Ilse van Ee |
Adviseur Patientenbelang - full time inbreng patientenperspectief |
Ervaringsdeskundige patientvertegenwoordiger - Eupati - fellow Psoriasispatienten Nederland - onbetaald Coordinator Patientenpraticipatie, lid centrale redactie Psoriasispatienten Nederland - onbetaald Eupati mentor - Eupati Nl - onbetaald |
nee |
nvt |
Janssen / Freedom of disease Psoriasis / ja |
nee |
nvt |
04/25/2025 |
|
|
Klaartje Caminada |
Medisch Manager Ambulancezorg, lid protocollencommissie Ambulancezorg Nederland |
geen |
geen |
geen |
geen |
geen |
geen |
04/29/2025 |
|
|
Brit Ketelaars |
Adviseur patiëntbelang bij Patiëntenfederatie Nederland (full time, betaald) |
geen |
geen |
geen |
geen |
geen |
geen |
04/25/2025 |
|
Inbreng patiëntenperspectief
De werkgroep besteedde aandacht aan het patiëntenperspectief door uitnodigen van Patiëntenfederatie Nederland, Geboortebeweging en Het Buikencollectiefvoor de invitational conference. Het verslag hiervan is besproken in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan Patiëntenfederatie Nederland en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uit om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).
Uit de kwalitatieve raming blijkt dat er waarschijnlijk mogelijk substantiële financiële gevolgen zijn, zie onderstaande tabel.
In Nederland bevallen per jaar ca. 160.000 vrouwen. De incidentie van haemorrhagia postpartum is 7 tot 10%. Dit zijn 11.200 tot 16.000 vrouwen per jaar. Het aantal vrouwen met risicofactoren voor HPP is niet bekend.
| Module |
Uitkomst raming |
Toelichting |
|
Fibrinogeen bij vrouwen met bloedverlies van 500 mL of meer postpartum |
geen financiële gevolgen |
Fibrinogeen substitutie wordt afgeraden voor de vroege behandeling van HPP |
Werkwijze
Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.
Zoekverantwoording
Algemene informatie
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Richtlijn: Richtlijn Modulaire actualisatie richtlijn Hemorrhagia Postpartum (HPP) |
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Uitgangsvraag: Wat is de rol van fibrinogeen bij vrouwen postpartum met bloedverlies van 500 ml of meer post partum? |
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Database(s): Medline (OVID), Embase |
Datum: 06-11-2023 |
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Periode: > 2000 |
Talen: geen beperking |
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Literatuurspecialist: Laura Boerboom |
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BMI zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/ Bij gebruikmaking van een volledig zoekblok zal naar de betreffende link op de website worden verwezen. |
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Toelichting en opmerkingen:
→ Voor deze vraag is gezocht op de elementen HPP (in het blauw) en fibrinogeen (in het groen).
→ Alle drie de sleutelpublicaties zitten in de resultaten.
→ Resultaten staan in Rayyan. |
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Te gebruiken voor richtlijnen tekst: In de databases Embase (via embase.com) en Medline (via OVID) is op 06-11-2023 met relevante zoektermen gezocht naar systematic reviews, RCT’s en observationele studies over wat de rol is van fibrinogeen bij vrouwen postpartum met bloedverlies van 500 ml of meer post partum. De literatuurzoekactie leverde 328 unieke treffers op. |
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Zoekopbrengst
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EMBASE |
OVID/MEDLINE |
Ontdubbeld |
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SR’s |
41 |
18 |
45 |
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RCT’s |
104 |
61 |
120 |
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Observationele studies |
155 |
85 |
163 |
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300 |
164 |
328 |
Zoekstrategie
Embase.com & Ovid/Medline
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Database |
Zoektermen |
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Embase
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Medline (OVID)
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1 exp Postpartum Hemorrhage/ or 'fluxus postpartum'.ti,ab,kf. or 'postpartum hemorrhage'.ti,ab,kf. or 'post partum haemorrhage'.ti,ab,kf. or 'post partum hemorrhage'.ti,ab,kf. or 'postpartal haemorrhage'.ti,ab,kf. or 'postpartal hemorrhage'.ti,ab,kf. or 'postpartum bleeding'.ti,ab,kf. or 'postpartum haemorrhage'.ti,ab,kf. or 'puerperal haemorrhage'.ti,ab,kf. or 'puerperal hemorrhage'.ti,ab,kf. or ('blood loss' adj6 (postpartum or 'post partum' or delivery or cesarean)).ti,ab,kf. or 'obstetric* bleeding'.ti,ab,kf. or 'obstetric* hemorrhage'.ti,ab,kf. or 'obstetric* haemorrhage'.ti,ab,kf. (14241)
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