NIfedipine levels in Mothers with and without PreEclampsia and their Newborns.

The placenta is the most crucial organ in the development of the fetus(1). Via
the placenta, the fetus receives oxygen and nutrients, while fetal waste is
removed via diffusion and active transport. To fulfill this task, the placenta
has a strict separation of the fetal and the maternal circulation.
Suboptimal development of the placenta may lead to severe complications of
pregnancy, most importantly pre-eclampsia (PE), characterized by elevated blood
pressure and proteinuria in the mother, potentially leading to maternal and
fetal morbidity and mortality (2, 3). Examination of placentas from PE
pregnancies shows structural changes in the placental blood vessels, such as
arterial vessel wall thickening and obstruction by atherosclerotic plaques,
resulting in increased placental vascular resistance and a reduction in
placental blood flow (4-6). The precise aetiology of the clinical symptoms of
PE is still largely unknown. However, we and others have demonstrated that
changes in the ratio of pro-angiogenic factors produced by the placenta,
probably in response to hypoperfusion, lead to a decrease in vascular
endothelial growth factor (VEGF) and an increase in endothelin-1 (ET-1), a
strong vasoconstrictor (7). ET-1 is thought to be responsible for the
hypertension and nephropathy in PE. ET-1 receptor blockers (ERAs), currently
used by patients with pulmonary hypertension, may therefore represent a novel
treatment option for PE. However, due to teratogenicity in animal models, ERAs
are currently contraindicated during pregnancy. Although suggested from the
vascular changes described above, it is currently unknown whether placental
drug transfer in general is different in hypertensive pregnancy disorders
compared to healthy placentas. To consider ERAs or other treatment options for
a clinical study in PE we first need to increase our knowledge about placental
drug transfer in general and in PE, which has not been studied before. For this
aim we will use a placental perfusion model (METC EMC-prg 1 2016-418). Since
direct comparisons between in vivo measurements and data obtained using the
model are scarce, we want to compare in vivo data (i.e. the drug concentration
in maternal and umbilical blood levels) with predicted data using the ex vivo
model.(8) For this purpose, we will use nifedipine as a model drug, since it is
used both in patients with gestational hypertension, in patients with PE and in
patients without hypertension who are at risk for premature birth.(9-11)
Nifedipine is (together with labetalol) used in pregnancy for decades as second
line option after methyldopa.(12) Limited PK data suggest that metabolism of
nifedipine is faster during pregnancy probably due to induction of
CYP3A4/5.(13, 14) Although placental transfer takes place this does not lead to
accumulation, however patients with or without hypertensive pregnancy disorders
have not been compared previously.(8) (14)
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Primary Objective:
To compare the fetal/maternal ratio of nifedipine blood concentrations between
pregnancies with and without hypertensive disorders, including preeclampsia.

Secondary Objective:
To compare predicted fetal/maternal drug ratios with observed fetal/maternal
drug ratios in pregnancies with and without a hypertensive pregnancy disorder
including preeclampsia.

The study will be a case-control study including both patients with
hypertension and suspicion of pre-eclampsia and patients at risk for preterm
birth (< 34 weeks of gestation). The study duration will be estimated one year,
the time needed to include eight women for each group for placental analysis.
Since patients with hypertension are at high risk of development of PE, we will
include these patients at the outpatient clinic. The maximum number of extra
venepunctures for this study will be two: one trough level in steady state, one
just before and one just after delivery. In addition, during regular vein
sampling an extra tube will be collected for pharmacokinetic modelling.

The procedure involves between three to five additional blood samples taken
from the mother dependent on the time between inclusion and delivery. The risk
is trivial. There is no direct benefit for the patient.