Urinary markers for fetal growth restriction: the role of gaseous vasoactive molecules.

Fetal growth restriction (FGR) is caused by placental insufficiency and occurs
in approximately 10% of all pregnancies. It is a major risk factor for short
-and long-term morbidity and mortality. Consequences include increased
incidence of various diseases, including hypertension and renal disease.
Predisposition for disease development originates in utero when the environment
programs the placenta and fetus by epigenetic mechanisms (Barker hypothesis).
A major issue in fetal growth restriction is the diagnostic process. Children
grown below a certain population based centile are either constitutionally
small or growth restricted. Children grown above that centile may be growth
restricted although their weight seems to be normal. If we use p10 as a cut
off we know that 50% of babies indicated as FGR are in fact healthy small
babies and we miss 50% of babies who are growth restricted and are grown above
the p10 (Voskamp et al., 2014). Ultrasound with combined biometrical and
Doppler measurements predict the occurrence of FGR and we can add functional
(invasive) parameters as PlGF and sFLit (Conde-Agudelo, Papageorghiou, Kennedy,
& Villar, 2013). These measurements are expensive and not widely available.
There is need for early predictors for FGR that are easy to measure,
inexpensive and, preferably, easy to sample. It is known that several gaseous
signaling molecules such as H2S, CO and NO play a role in the (compensatory)
mechanism of FGR since they are involved in blood pressure regulation,
inflammation and reactive oxygen (ROS) scavenging. These molecules and their
metabolites are of our interest since recent work in renal transplant patients,
heart failure patients, diabetic patients, healthy individuals and patients
with placental insufficiency. It has shown that gaseous signaling molecules
predict mortality and disease outcome. Whether H2S is a cause or a consequence
of placental insufficiency is unknown. In this pilot study we aim to find a
predictive marker for FGR that is easily available, non-invasive and
inexpensive.

Hypothesis: gaseous signaling molecules influence placental vasomotor activity
to compensate for hypoxemia. Metabolites of these vasoactive molecules can be
found in the blood and urine and can indicate whether this (compensatory)
mechanism is used to enhance placental function.

Objective:
To measure urinary and blood metabolites of gaseous vasoactive molecules in
complicated and uncomplicated pregnancy to define a novel biomarker for FGR.

Blood samples are taken the day after the urine collection when the patient
brings the urine container to the outpatient clinic. In case the patient is
hospitalised, also the blood sample is taken the day after the urine
collection. Placental biopsies, placental bed biopsies (in case of caeserean
section) and umbilical cord blood are all taken just after delivery.

Blood samples will not possess any risk. Urine samples will possess no risk
either. Placenta: no risk, Placenta bed biopsies and placental biopsies: no
risk. Umbilical cord blood samples are taken from the umbilical artery after
birth of the placenta, which will otherwise be discarded: no risk for the
patient.