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Antidepressants During Pregnancy and Lactation: Pharmacokinetics and Clinical Implications

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Centre Hospitalier Universitaire Vaudois
Sponsor:
Collaborators:
University Hospital, Geneva
Hospices Civils de Lyon
Central Hospital, Nancy, France
Information provided by (Responsible Party):
Chantal Csajka, Centre Hospitalier Universitaire Vaudois
ClinicalTrials.gov Identifier:
NCT01796132
First received: February 4, 2013
Last updated: February 17, 2014
Last verified: February 2014
  Purpose

Background: The childbearing years are a time of increased vulnerability to the onset of mood disorders in women and a high prevalence of exposure to antidepressant drugs during pregnancy and postpartum has been reported. However, the lack of information regarding the milk transfer and the safety of these drugs in breastfed infants and the related fear of adverse events for the sucking infant are some of the factors responsible for stopping prematurely breast-feeding or avoiding drug therapy. Selective serotonin reuptake inhibitors (SSRI) and selective serotonin and noradrenaline reuptake inhibitors (SNRI) are the most frequently prescribed antidepressant drugs during pregnancy and the post-partum period. They exhibit a wide interpatient variability in their concentration profiles that has been related to numerous environmental, stereochemical, demographic and genetic influences that might alter the level of exposure of breastfed newborns. Limited information is available regarding the safety of use of these antidepressant drugs during lactation, and is generally derived from small studies. A comprehensive description of their distribution and quantification in milk in a larger cohort of patients under various influences and the resulting impact on milk concentrations is lacking.

Objectives: The current proposal addresses the primary objectives of quantifying the range of concentration to citalopram, escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine, duloxetine and venlafaxine in mother plasma and breast milk in relation to genetic polymorphisms, stereochemistry, demographics and environmental factors in a large cohort of depressive mothers. This will enable to derive the exposure to the breast-fed child taking into account this variability and therefore better adjust treatment to potential influences. As secondary objectives, we will examine the neurodevelopmental outcome of a sub-set of infants subjected to SSRI/SNRI in utero and/or during breastfeeding at birth, 6, 18 and 36 months, and compared to that of a control population of infants not subjected to this treatment.

Expected Results: The proposed strategy will offer new information regarding the expected level of drug exposure associated with each or with a combination of risk factors and help for optimizing the security and rationalizing the use of antidepressant treatment in lactating women. Hence, research on the safety of use of these drugs for the developing child is an area of great public health significance.


Condition Intervention Phase
Depressive Disorder
Lactation
Drug: SSRI/SNRI
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Antidepressant Treatments During Pregnancy and Lactation: Prediction of Drug Exposure Through Breastfeeding and Evaluation of Drug Effect on the Neonatal Adaptation and the Development of the Young Child

Resource links provided by NLM:


Further study details as provided by Centre Hospitalier Universitaire Vaudois:

Primary Outcome Measures:
  • Evaluate the pharmacokinetics of SSRI/SNRI antidepressant drugs in breast milk secretion [ Time Frame: week 1 and week 4-6 postpartum ] [ Designated as safety issue: No ]

    The principal aim is to derive exposure to the breast-fed child by simulation while integrating influencing factors on pharmacokinetics (as genetic polymorphism, stereochemistry, demographics or environmental aspects).

    5ml blood, 10ml fore-milk and 10ml hind-milk are taken from the mother during the same feed at week 1 and week 4-6 postpartum. Antidepressant drug concentrations are determined by LC-MS/MS and milk composition by human milk analyzer.Pharmacogenetic tests are performed with PCR-Taqman on maternal blood samples and cover genes involved in the metabolism (e.g CYP) and distribution (e.g. p-Gp) of antidepressants. Simulation of antidepressant drug secretion into breast milk will take into account all this information and will be performed with non-linear mixed effects modelling techniques.



Secondary Outcome Measures:
  • Examine neonatal adaptation [ Time Frame: delivery and week 1 postpartum ] [ Designated as safety issue: Yes ]

    The specific aim is to evaluate neonatal adaptation after in utero exposure to antidepressants and its relation to cord blood concentration.

    5ml blood are taken from the umbilical cord and the mother at delivery. Antidepressant drug concentrations are determined by LC-MS/MS. Finnegan Score is used to evaluate the severity of possible withdrawal or discontinuation syndrome in exposed newborns.


  • Examine neurodevelopment [ Time Frame: week 1, month 6, 18 and 36 postpartum ] [ Designated as safety issue: Yes ]

    The specific aim is to evaluate neurodevelopment of a sub-set of infants exposed to any SSRI/SNRI in utero and/or during breastfeeding compared to a control population of infants not exposed to this treatment.

    During week 1 postpartum, somatic and neurologic state of the newborn are evaluated by a pediatrician using routine measures as well as specific tools (Dubowitz's neurologic assessment, Prechtl's general movements). At month 6,18 and 36, neurodevelopment of the infants are assessed using Hammersmith Infant Neurological Examination and Bayley Scales of Infant Development III. At the same time, mother's mental well-being is determined by using self-administered questionnaires (Edinburgh Postnatal Depression Scale, State-Trait Anxiety Inventory, Parental Sens of Competence and Revised Infant Temperament Questionnaire).


  • Study of growth [ Time Frame: birth, month 6, 18 and 36 postpartum ] [ Designated as safety issue: Yes ]

    The specific aim is to evaluate growth of infants exposed to any of the SSRI/SNRI commercialized, compared to standardized growth charts.

    Usual infant growth information (size, body weight, head circumference) are collected routinely at birth and month 6,18,36.


  • Examine early mother-infant relationship [ Time Frame: Month 6 postpartum ] [ Designated as safety issue: Yes ]

    The specific aim is to explore the quality of early mother-infant relationship of a sub-set of infants whose mothers are treated with SSRI/SNRI, compared to that of a control population of infants not exposed to this treatment.

    At month 6 postpartum, mother-infant relationship is evaluated by pedopsychiatrists using Care Index.



Estimated Enrollment: 500
Study Start Date: August 2012
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Control
Pregnant and/or nursing mothers not taking a SSRI or SNRI antidepressant are recruited in a non-exposed group (Control or no SSRI/SNRI). Control group participates only in the sub-studies related to neonatal adaptation, neurodevelopment, growth and early mother-infant relationship.
Experimental: SSRI/SNRI exposure
Pregnant and/or nursing mothers under SSRI or SNRI treatment are recruited in an exposed group (SSRI/SNRI exposure). Drug regimen including dosage, frequency and duration is not modified by the study.
Drug: SSRI/SNRI
Exposed group of mothers taking one of the mentioned antidepressant drugs of the class of selective serotonin reuptake inhibitors (SSRI) or serotonin/noradrenalin reuptake inhibitors (SNRI).
Other Names:
  • citalopram
  • duloxetine
  • escitalopram
  • fluoxetine
  • fluvoxamine
  • paroxetine
  • sertraline
  • venlafaxine

Detailed Description:

see brief summary

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients planning to deliver in the 5 maternities involved in the study;
  • Mothers under treatment by any SSRI/SNRI (fluvoxamine, fluoxetine, paroxetine, duloxetine, citalopram, escitalopram, sertraline or venlafaxine);
  • Mothers who intent to breastfeed their child;
  • Ability to understand and willingness to sign a written informed consent document for plasma and milk withdrawal and pharmacogenetic testing.
  • For the neurodevelopment follow-up part,all babies of the Maternity of Lausanne, Morges or Geneva exposed to SSRI/SNRI will be enrolled. A control group of infants of the same socio-economic status as the subset of exposed patients will be recruited in the Maternity Hospital of Lausanne.

Exclusion Criteria:

  • Mothers <18 years of age patients;
  • Infants of gestational age < 34 weeks;
  • Mothers giving birth to infants with major malformations;
  • Inability to communicate due to language problems for the mother;
  • Patients with a socio-economic context making close monitoring of the child by the mother or a relative not possible.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01796132

Contacts
Contact: Chantal Csajka, Prof PhD 0041 21 314 42 63 chantal.csajka@chuv.ch
Contact: Alice Panchaud, PhD 0041 21 314 42 76 alice.panchaud@chuv.ch

Locations
France
Service d'Obstétrique, Service de Néonatologie; Centre Hospitalier Universitaire Nancy Recruiting
Nancy, Meurthe-et-Moselle, France
Contact: Jean-Michel Hascoët, Prof MD       jm.hascoet@maternite.chu-nancy.fr   
Principal Investigator: Jean-Michel Hascoët, Prof MD         
Sub-Investigator: Catherine Lamy, MD         
Service d'Obstétrique, Service de Néonatologie; Hospices civiles de Lyon (HCL) Recruiting
Lyon, Rhône, France
Contact: Olivier Claris, Prof MD       olivier.claris@chu-lyon.fr   
Principal Investigator: Olivier Claris, Prof MD         
Sub-Investigator: Pascal Gaucherand, Prof MD         
Sub-Investigator: Etienne Beaufils, MD         
Sub-Investigator: Kim NGuyen, MD         
Switzerland
Division de Pharmacologie Clinique, Service d'Obstétrique, Service de Néonatologie, Service de Pédopsychiatrie de liaison, Unité de Pharmacogénétique et Psychopharmacologie Clinique; Centre Hospitalier Universitaire Vaudois (CHUV) Recruiting
Lausanne, Vaud, Switzerland
Contact: Chantal Csajka, Prof PhD       chantal.csajka@chuv.ch   
Principal Investigator: Chantal Csajka, Prof PhD         
Sub-Investigator: Alice Panchaud, PhD         
Sub-Investigator: Chin B Eap, Prof PhD         
Sub-Investigator: Jean-Francois Tolsa, Prof MD         
Sub-Investigator: Yvan Vial, MD MER         
Sub-Investigator: Myriam Bickle Graz, MD         
Sub-Investigator: Mathilde Morisod Harari, MD         
Sub-Investigator: Céline Fischer, MD         
Service d'Obstétrique, Service de Pédiatrie; Ensemble Hospitalier de la Côte (EHC) Recruiting
Morges, Vaud, Switzerland
Contact: Sylvie Rouiller, MD       sylvie.rouiller@ehc.vd.ch   
Principal Investigator: Sylvie Rouiller, MD         
Service d'Obstétrique, Service du Développement et de la Croissance; Hopitaux Universitaires Genevois (HUG) Recruiting
Geneva, Switzerland
Contact: Manuella Epiney, MD       manuella.epiney@hcuge.ch   
Principal Investigator: Manuella Epiney, MD         
Principal Investigator: Cristina Borradori Tolsa, MD         
Sponsors and Collaborators
Centre Hospitalier Universitaire Vaudois
University Hospital, Geneva
Hospices Civils de Lyon
Central Hospital, Nancy, France
Investigators
Principal Investigator: Chantal Csajka, Prof PhD Centre Hospitalier Universitaire Vaudois (CHUV)
  More Information

Publications:

Responsible Party: Chantal Csajka, Prof PhD, Centre Hospitalier Universitaire Vaudois
ClinicalTrials.gov Identifier: NCT01796132     History of Changes
Other Study ID Numbers: SSRI-Milk, 320030_135650, 2012-004509-29
Study First Received: February 4, 2013
Last Updated: February 17, 2014
Health Authority: Switzerland: Swissmedic
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Centre Hospitalier Universitaire Vaudois:
Depression
Lactation
Breastfeeding
Pharmacokinetics
Antidepressant

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mental Disorders
Mood Disorders
Antidepressive Agents
Central Nervous System Agents
Pharmacologic Actions
Psychotropic Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014