Clinical trial NCT06049953: Maternal And Infant Antipsychotic Study
Official title: Developmental Effects of Antenatal Exposure to Antipsychotics
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Antipsychotics
Pregnancy
Keywords: antipsychotic
pregnancy
severe mental illness
neonatal adaptation syndrome
neurodevelopment
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2023-09-22
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pregnant women with severe mental illness as defined in Eligibility Criteria

Brief summary: The goal of this observational study is to learn about maternal psychiatric course and infant development in pregnant individuals with severe mental illness, comparing those treated with antipsychotics to those treated with other medications or without medication. The main questions it aims to answer are:

1. Is risk of psychiatric relapse different among individuals who take antipsychotic medication, other medication, or no medication?
2. Are pregnancy and neonatal health outcomes different among individuals who take antipsychotic medication, other medication, or no medication?
3. Do infant behavior and neurodevelopment differ among babies who were exposed to antipsychotic medication, other medication, or no medication in utero? Participants will

   * complete a psychiatric interview and questionnaires while pregnant;
   * donate blood from the mother and from the umbilical cord at delivery
   * have their babies participate in infant behavior evaluations and an EEG procedure.

Researchers will compare these outcomes among individuals who were treated either with antipsychotic medication, with psychotropic medications of other classes, and with no medication, to see if psychiatric benefits for the mother and health outcomes for mother and child differ among these three types of treatment.

Detailed description: Antipsychotic (AP) medications are widely prescribed for a range of mental illnesses including bipolar disorder and nonaffective psychosis. These disorders usually onset in adolescence or early adulthood; thus, women of childbearing age are among those prescribed APs. The number of pregnancies exposed to APs has been increasing over time. Yet their efficacy has never been definitively demonstrated in this population.

APs cross the placenta and block dopamine (DA) D2 receptors, which are functional in the developing fetus, including influencing the proliferation and differentiation of neural progenitor cells. 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. Additionally, gestational diabetes mellitus (GDM) is an established short-term risk of AP in pregnancy, which is associated with both increased body size and impaired cognitive and motor development in offspring.

At present very limited data exist on developmental outcomes associated with antenatal exposure to APs. Infant studies have found some evidence of initial difficulty adapting to life outside the womb as well as early neuromotor problems, but existing studies lack adequate comparison groups, and longitudinal data are lacking. Regarding long-term outcomes, the research group has found sex-specific increases in risk for psychiatric disorders for male, but not female, offspring, in both a register-based dataset and a clinical pilot study. This potential neurodevelopmental vulnerability requires further investigation in a rigorous longitudinal cohort study.

This study aims to investigate efficacy and adverse effects of AP exposure in pregnant women with severe mental illness (SMI). The research team hypothesizes that APs will be efficacious for psychiatric disorders, but will be associated with increased weight gain in mothers, poor neonatal adaptation in neonates, and sex-specific neurodevelopmental changes in infants. The 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 Aims:

Aim 1: To investigate efficacy and adverse effects of AP treatment for pregnant women.

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 have greater weight gain in pregnancy than women taking non-APs or women taking no medication.

Researchers will recruit women in pregnancy with SMI (bipolar or primary psychotic disorder, N=200) in three groups: taking AP, taking other psychotropic medication, and taking no psychotropic medication, via two specialized perinatal psychiatric centers in NYC and the Netherlands. Women will be followed naturalistically and assessed for psychiatric relapse in pregnancy and the postpartum period, as well as complications of pregnancy, including weight gain and gestational diabetes, This will be the first study of AP efficacy in pregnancy.

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 psychotropics 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 psychotropics or no medication. The research team 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. This will be the first controlled study of NAS after antenatal AP exposure.

Aim 3: To describe neurobehavioral development through 6 months in children from Aim 2. Aim 3a: Auditory sensory gating in children exposed to AP antenatally. Hypothesis: All infants prenatally exposed to APs will have reduced inhibitory activity as measured by the P50 component in the EEG. Aim 3b (Exploratory): Neurobehavioral development through 6 months in children exposed to AP antenatally. Hypothesis: Researchers predict increased symptoms of anxiety and internalizing behaviors for males only. Reduced auditory sensory gating will mediate, and sex will moderate, socioemotional outcomes associated with AP exposure. Comprehensive interviews, behavioral observations, and electroencephalography (EEG) obtained in a home visit at 6 months will assess socioemotional, cognitive, and motor development. The research team will investigate whether infant sex moderates any observed effects of AP exposure. This will be the first study of neural activity after antenatal AP exposure.

Eligibility criteria: Inclusion Criteria:

* Pregnant
* Severe mental illness, including:

  * Psychotic disorder (affective and nonaffective)
  * Bipolar disorder
  * History of psychiatric hospitalization, regardless of diagnosis
* Able to complete study interviews and measures in English, Dutch, or Spanish

Exclusion Criteria:

* Active substance use disorder in pregnancy
* Insufficiently high-functioning to provide full informed consent and/or participate in study procedures

Primary outcomes:
measure: Mini-International Neuropsychiatric Interview
timeFrame: through study completion, an average of 6 months postpartum
measure: Finnegan Neonatal Abstinence Scoring System
timeFrame: 24 hours postnatal
measure: Ratio of auditory evoked potentials as measured by EEG
timeFrame: 6 months postnatal
Secondary outcomes:
measure: Maternal weight gain
timeFrame: through delivery, approximately 40 weeks post conception
measure: Oral glucose tolerance test score
timeFrame: at 24 weeks
measure: Fetal body size
timeFrame: at 20 weeks
measure: Fetal weight
timeFrame: at 20 weeks
measure: Fetal head circumference
timeFrame: at 20 weeks
measure: Fetal biparietal diameter
timeFrame: at 20 weeks
measure: Fetal cerebellar diameter
timeFrame: at 20 weeks
measure: Neonatal birth weight adjusted for gestational age at delivery, as a percentile score
timeFrame: at 20 weeks
measure: Fetal femur length
timeFrame: at 20 weeks
measure: Neonatal body size
timeFrame: at delivery
measure: Neonatal length
timeFrame: at delivery
measure: Neonatal weight
timeFrame: at delivery
measure: Neonatal head circumference
timeFrame: at delivery
measure: Changes in Infant length percentile
timeFrame: at delivery and 6 months postnatal
measure: Changes in weight percentile
timeFrame: at delivery and 6 months postnatal
measure: Bayley-III Score
timeFrame: at 6 months postnatal
measure: Vineland Interview
timeFrame: at 6 months postnatal
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Thalia Robakis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: