PANDA-study - Prenatal And Neonatal Development: An offspring study of severe mental illness

Severe mental illness, including schizophrenia, bipolar disorder, and major
depressive disorder, contribute significantly to overall disability adjusted
life years. The risk of severe mental illness is especially high for offspring
of parents affected by these disorders* they have a 2-to-3 fold increased risk
to develop psychotic, mood, anxiety, and externalizing disorders. In the
Netherlands, 577.000 children and adolescents are at such high risk (NEMESIS2).
In the US, this number is close to three million. At present, there are
critical knowledge gaps that hamper the implementation of clinical and public
health strategies to alleviate this risk despite the pronounced and obvious
public health ramifications. Accurate detection, diagnosis, and treatment as
early in life as possible is needed. To accomplish this, we propose to
investigate very early brain development, i.e., during the fetal and neonatal
period, which we hypothesize to underlie future onset of severe mental illness.
Given that magnetic resonance imaging (MRI) and ultrasonography are
complementary techniques, using both techniques is essential for complete
evaluation of the fetal brain. Moreover, adding MRI to ultrasound allows us to
examine fetal to neonatal brain growth trajectories in a continuous manner as
ultrasound is no longer possible after birth.

Primary:
- Investigate the feasibility of examining fetal and neonatal brain
developmental trajectories in the fetus and neonate with at least one parent
with SMI in the mood-psychosis spectrum (vs. parents without SMI) using MRI.
- Acquire preliminary data to investigate whether differences in brain
developmental trajectories between offspring of parents with and without SMI
can be detected using MRI and ultrasound.

Secondary:
- Investigate how features of fetal and neonatal brain development relate to
clinical features in the affected parent and/or home environment, as well as
parental bonding and offspring development over time.
- Investigate how polygenic risk scores for psychiatric traits and cortical
levels in parents and offspring influence early brain developmental
trajectories in offspring.

Longitudinal case-control study, family design

Study participation involves undergoing an MRI scan of maximally 30 minutes:
two times for the pregnant woman and one time for the neonate. The pregnant
woman will also undergo an ultrasound scan of maximally 30 minutes. For women
who receive obstetric care in the Erasmus MC the visits will be combined as
much as possible with already planned visits (e.g. for antenatal care). To make
the MRI procedure as comfortable as possible for the mother and newborn, we
will use appropriate positioning, and specifically for the newborn swaddling
and timing of feeds, to help optimize effective scanning. We will not use
pharmacological sedation or general anesthesia.

The risks for participation in this study are negligible. The ultrasound
techniques that we will be using are safe and harmless. Worldwide ultrasound is
routine antenatal care. No risks of ultrasound to the mother nor to the fetus
or newborn have been described to date. Moreover, MRI is generally accepted as
safe, both in pregnancy and in neonates, based on extensive experience (Lum &
Tsiouris, 2020; Ray et al., 2016; Tocchio et al., 2015). Therefore, no special
preparation for the subject on top of the Erasmus MC standard procedure is
needed. Both MRI in pregnancy and MRI in neonates have been approved by the
METC in previous studies led by members of the research team [METC protocol ID:
MRI in pregnancy: NL65570.000.18; MRI in neonates: NL67183.078.19].

Participants will experience no direct benefits from our study. In the long
run, increased understanding of the etiology and pathophysiology of mental
disorders on the mood-psychosis spectrum may contribute to diagnosis, early
detection and/or prediction of treatment outcome.