Veiligheid en werkzaamheid van nadroparine in neonaten. een observationele studie

The incidence of venous thrombosis is rising rapidly in neonates.[1,2] This
rise is the result of improved neonatal care over the past 20 years resulting
in an increase in the survival of (extremely) premature and critically ill
infants. When a venous thrombus occurs there is an indication for therapeutic
anticoagulant treatment (anti Xa levels 0.5-1.0 IU/mL). Inhibition of the
coagulation system gives the opportunity to resolve the clot. If neonates are
at high risk for venous thrombosis preventive measures can be taken by
prophylactic anticoagulant treatment (anti-Xa levels 0.1-0.4 IU/mL). This
inhibits the coagulation system in a lesser way compared to therapeutic
anticoagulant treatment and prevents formation of a thrombus.
In the Netherlands each year 250 neonates receive off-label therapeutic and
prophylactic nadroparin treatment, without any information on the
pharmacokinetics/-dynamics (PK/PD) and therefore optimal and safe dosage
regimen. As a result, these neonates are prone to suboptimal treatment with a
risk for thrombosis, a lack of thrombus resolution or major bleeding.
Therefore we designed an observational study during standard care to objectify
the PK/PD in neonates.

Therapeutic nadroparin administration:
Primary objective:
To develop evidence-based dosing regimens of nadroparin for extremely
premature, premature and term neonates by means of the objectification of the
PK/PD of nadroparin.
Secondary objective:
1) Investigate the relation between anti Xa levels and thrombus resolution
within 3 months after the start of nadroparin treatment
Investigate the relation between anti Xa levels and bleeding during treatment
with nadroparin until 24 hours after termination of nadroparin
Prophylactic nadroparin administration:
Primary objective:
To develop evidence-based dosing regimens of nadroparin for premature and term
neonates by means of the objectification of the PK/PD of nadroparin.
Secondary objective:
1) Investigate the relation between anti Xa levels and new or recurrent
thrombosis during treatment with nadroparin

A national observational prospective study, conducted in 6 Neonatal Intensive
Care Units/ Children*s Hospitals in the Netherlands.

As mentioned above, each year 250 neonates receive off label nadroparin
treatment without any information on PK/PD and therefore optimal and safe
therapeutic or prophylactic dosage regimen. Despite this off label treatment,
dosage recommendations have been provided. As a result, these neonates are
prone to suboptimal treatment with a risk of a new thrombosis, a lack of
thrombus resolution, or major bleeding. This bleeding has an impact on the
morbidity and survival of neonates Therefore we will perform an observational
study during standard care to objectify the PK/PD in neonates. With the
development of evidence-based therapeutic dosing regimens for extremely
premature, premature and term neonates, and evidence-based prophylactic dosing
regimens for premature and term neonates for nadroparin we can ensure these
vulnerable neonates an effective treatment without toxicity, and therefore less
complications. A possible risk is reducing the circulating blood volume of
neonates by taking blood. Therefore we minimized the volume blood samples (5 mL
in total per neonate). To avoid the burden of venepunctures we aim to include
mainly neonates with central venous or arterial access and combine blood
samples with standard blood samples.