Developmental Effects of Antenatal Exposure to Antipsychotics

Antipsychotic (AP) medications are widely prescribed for a range of mental
illnesses including bipolar disorder and non-affective psychosis (1,2). These
disorders usually onset in adolescence or early adulthood (3); thus, women of
childbearing age are among those prescribed APs. The number of pregnancies
exposed to APs has been increasing over time (4,5,6). In the USA, prevalence of
AP use in pregnancy increased from 0.3-0.4% to 0.8-1.3% (4,5) over the first
decade of the twenty-first century. APs cross the placenta, and in some cases
the fetus is exposed to a higher concentration than the mother*s serum level
(7). APs block dopamine (DA) D2 receptors, which are functional in the
developing fetus (8), including influencing the proliferation and
differentiation of neural progenitor cells (9). Increased DA signaling in early
development results in increased numbers of inhibitory cortical interneurons
and decreased numbers of pyramidal cells, while decreased DA signaling has the
reverse effect. Thus, tonic DA blockade in utero could alter the
excitatory/inhibitory balance in mature prefrontal cortex, which could affect
fear processing, social functioning, and spatial or working memory in the long
term. At present very limited data exist on developmental outcomes associated
with antenatal exposure to APs (10). This study aims to investigate efficacy
and adverse effects of AP exposure in pregnant women with severe mental illness
(SMI). Our overall goal is to precisely describe the risk/benefit ratio
associated with AP treatment in pregnancy, in order to allow pregnant women
with SMI to make informed decisions about their care.

Primary Objective:
To investigate efficacy and adverse effects of AP treatment for pregnant women
with SMI.

Aim 1a: Efficacy of AP treatment for pregnant women with SMI.
Hypothesis: Women taking either APs or non-AP mood stabilizers will be less
likely to relapse with mood or psychotic episodes than those not medicated.

Aim 1b: Adverse pregnancy outcomes with AP treatment for pregnant women.
Hypothesis: Women taking Aps will be more likely to develop gestational
diabetes than women taking non-APs or women taking no medication.

We will recruit women in pregnancy with SMI (bipolar or primary psychotic
disorder, in three groups: women taking AP, women taking other psychotropic
medication, and women taking no psychotropic medication. Women will be followed
naturalistically and assessed for psychiatric relapse in pregnancy and the
postpartum period, as well as complications of pregnancy, including gestational
diabetes, pre-eclampsia, and hemorrhage.

Secondary Objectives:

Aim 2:To describe neonatal adaptation and physical growth in neonates of the
mothers either exposed or unexposed to APs during pregnancy.

Aim 2a:Neonatal adaptation in neonates either exposed or unexposed to APs
during pregnancy.
Hypothesis: Neonates of mothers who took APs during pregnancy will evince
poorer neonatal adaptation than neonates of mothers who took either non-AP
psychotropic medication or no medication.

Aim 2b:Physical growth in neonates either exposed or unexposed to APs during
pregnancy.
Hypothesis: Neonates of mothers who took APs during pregnancy will have larger
body sizes than neonates of mothers who took either non-AP psychotropic
medication or no medication.

We will examine obstetric and neonatal outcomes of infants of women with SMI,
including neonatal adaptation syndrome (NAS), with control for maternal
diagnosis and level of functioning.

Aim 3: To investigate sensory gating and development through 6 months in
children of the mothers either exposed or unexposed to APs during pregnancy.

Aim 3a: To investigate sensory gating in children exposed to AP antenatally.
Hypothesis: All infants prenatally exposed to APs will have reduced inhibitory
activity as demonstrated by reduced auditory sensory gating, measured by the
P50 component in the EEG.

Aim 3b (Exploratory): Investigation of development through 6 months in children
exposed to AP antenatally.
Hypothesis: We expect to find lower scores on the Socialization Domain of the
Vineland and on the Social-Emotional scale of the Bayley. Further we
hypothesize that we might find a sex specific effect for the associations
between socioemotional outcomes associated with AP exposure.

Aim 3c (Exploratory): Investigate how biological and (epi-)genetic factors in
parents and offspring influence development in offspring.

Aim 4 (Exploratory): To describe AP serum level changes during the peripartum
period in mothers.
Hypothesis: We expect serum level fluctuations during pregnancy and postpartum
period as a result of blood volume changes in mothers.

Design: Longitudinal naturalistic prospective cohort study
Duration: 5 years
Follow up: from first trimester of pregnancy until 6 months postpartum
Setting: Women treated in outpatient reproductive psychiatric and obstetric
clinics of the Erasmus Medical Center in the Netherlands and at Mount Sinai NY,
USA .

This study will be a longitudinal clinical cohort study to investigate efficacy
and adverse effects of AP exposure in pregnant women with serious mental
illness (SMI).
Our overall goal is to precisely describe the risk/benefit ratio associated
with AP treatment in pregnancy, in order to allow pregnant women with SMI to
make informed decisions about their care.

Study assessments are optimally aligned with routine clinical care. There are
no risks associated with an one hour diagnostic interview. The risks of
obtaining a venous blood sample can be considered negligible. Blood sampling is
combined with clinical blood withdrawals as much as possible. To our knowledge
there are no medical risks associated with an EEG. Collection times coincide as
much as possible with regular care.