November 12-13, 2003
Holiday Inn Select
Bethesda, MD
This meeting was held in conjunction with the National Children’s Study, which is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS], two parts of the National Institutes of Health, and the Centers for Disease Control and Prevention [CDC]) and the U.S. Environmental Protection Agency (EPA).
Review of Meeting Goals and Agenda
Mark A. Klebanoff, M.D., M.P.H., NICHD, NIH, DHHS, explained that the Pregnancy and the Infant Working Group developed two hypotheses at a prior meeting. One hypothesis concerned the effect of infection on pregnancy and outcome, and the other was the core hypothesis concerning stress:
Excessive maternal psychosocial stress during pregnancy, in conjunction with maternal and fetal genetic susceptibilities, is reflected in specific measures of biologic function and results in an altered trajectory of fetal growth and development. These consequences predispose to adverse outcomes, such as preterm birth, fetal/infant demise, cognitive/neurobehavioral dysfunction, and adult onset of cardiovascular disease.
The purpose of this workshop was to define stress, identify measures of stress exposure to the mother (preconception through postpartum), fetus, and infant, and clarify measures of the stress response in the mother (preconception through postpartum), fetus, and infant.
Group A: Mother from Preconception through Postpartum
Objective 1: Define Stress and Sources of Stress
The group decided to refine the definition of stressor, because not all stress is threatening or illness producing and the positive effects from stress exposure have not been extensively studied. The group identified three components of stress—stressor, appraisal, and response. This multifactorial and dynamic process involves interrelationships among all three components. After discussion, the group developed the following definitions:
- Stressor: Any physical or psychological demand or challenge that alters or has the potential to alter the internal milieu of the organism (homeostasis).
- Appraisal: Cognitive appraisal or perception of the demand or challenge.
- Response: The resulting individual behavioral, emotional, cognitive, or physiological adaptation that occurs in response to a demand or challenge. This response may be adaptive or maladaptive.
Objective 2: Itemize and Discuss Mechanisms of Stress on Maternal Pregnancy and Fetal Development
The group identified the following systems that are affected by exposure to stress during pregnancy:
- Allostatic load.
- Placental synthesis of adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH). Stress-induced elevation of CRH increases likelihood of preterm birth.
- Autonomic nervous system.
- Catecholamines (primarily norepinephrine) that affect blood flow to the placenta by increasing vascular resistance (measuring urinary levels is least intrusive for the patient).
- Neuroendocrine system (cortisol levels can cross the placenta and directly affect fetal growth; measuring salivary levels is not intrusive).
- Immune system function (immunosuppression and anti-inflammatory response).
- Urinary artery resistance/vasoconstriction.
- Counter-regulatory mechanisms.
- Genetic polymorphisms, gene-environment interactions, and gene expression.
- Maternal behavior (drug use, caretaking).
- Maternal psychological processes.
Objective 3: Define and Select Exposure Measures
The group agreed that measures to evaluate exposures should be germane to pregnancy; be shown to have high validity across varying ethnic groups, socioeconomic levels, urban/rural settings, and religions; and include psychometric properties that have low subject burden. Examples of exposures to stress during pregnancy included:
- Major life events
- Structural factors such as low income, education, occupational status, and ethnicity
- Living conditions including housing, transportation, medical care, and nutritional status
- Work (physical and psychological demands)
- Relationships and social support
- Pregnancy stressors
- Child/family responsibilities and marital status
- Violence (domestic and otherwise)
- Neighborhood conditions.
The above stressors are listed separately but are often measured collectively, sometimes by the same instrument. The necessity of creating a conceptual framework to permit measurement of outcomes and to identify measures that will serve multiple functions was an ongoing theme throughout the discussion of measures. Because the Study will have a large and diverse sample, the group emphasized the merit of using small studies to evaluate measurement tools for various socioeconomic, cultural, and geographic groups.
Objective 4: Define and Select Response Measures
The group concluded that responses to stressful stimuli fall into four broad categories—emotional, behavioral, cognitive, and physiological. For the purposes of the Study, emotional responses that can be evaluated include anxiety, depression, anger, impaired relationships, and psychopathology (including post-traumatic stress disorder). Measurable behavioral responses are health behaviors, medical adherence, dietary practices, sleep disturbances, and sexual activity. Cognitive responses discussed were rumination, cognitive coping, attitudes toward the infant, and memory impairment during pregnancy. Several aspects of physiological responses to stress during pregnancy were presented and discussed:
- Endocrine: HPA axis, immunity, illness, oxytocin, glucocorticoids, growth hormone, catecholamines, endorphins, CRH
- Cardiovascular:reactivity, heart rate variability (vagal), blood pressure, blood flow, lipid levels
- Metabolic: insulin resistance, caloric utilization, metabolic syndrome, glucose levels, abdominal fat, bone density
- Nervous: hyperarousal, depression, anxiety, cognition, catecholamines.
Moderators of stress responses that can buffer or exacerbate the response to the above exposures include disposition/personality (optimism, resilience, trait anxiety), mental health, physical health, family health, social support, coping, physiological reactivity, religiosity, and acculturation.
Recommendations
During the second day of the workshop, Group A participants divided appraisal and response measures into prioritized lists and further subdivided the lists into recommendations for inclusion in the overall Study or smaller studies.
Psychosocial Stimuli/Appraisal Measures for the Large Study
1. Major life events (number and distress from)
2. Life strain (anxiety, pregnancy-specific stress, relationships, and social support)
3. Demographics (income, education, occupation, marital status, responsibilities, and neighborhood conditions).
Stress Response Measures for the Large Study
- Emotional: anxiety, depression, anger, and impaired social relations
- Health behaviors: medical adherence, substance abuse, diet, sexual behavior, physical activity, smoking, self-medication
- Increased somatic complaints without identified cause
- HPA axis (salivary cortisol)
- Cardiovascular: blood pressure, vascular resistance (uterine, umbilical artery, middle cerebral artery), lipids, ACTH/androgen ratios, heart rate variability (vagal), and pulse pressure waveform
- Metabolic: fasting glucose insulin tolerance, metabolic syndrome
- Waist-hip ratio before 15 weeks, body mass index (BMI).
Suggestions for Pilot Studies on Responses
- Laboratory reactivity of both mother and fetus (including startle)
- Detailed HPA axis and catecholamine studies
- CRH-binding proteins
- Circadian salivary assessments
- Biomarkers for health behaviors
- Cardiovascular assessments
- Extended battery of paper-and-pencil psychosocial assessments
- Lipopolysaccharide measure from blood draw
- Measure of anti-inflammatory response
- Cognition (rumination, cognitive coping, memory impairment).
Highest Priority Moderator Measures for the Large Study
- Disposition/personality (trait anxiety or optimism)
- Trait hostility
- Religiosity.
Suggestions for Pilot Studies on Moderators
- Daily hassles
- Perceived racism
- Role conflict (work, family)
- Work stress (demand, control)
- Sexism and sexual harassment
- Acculturation.
Group B: Fetus through Early Childhood
Objective 1: Define Stress and Sources of Stress
The group noted the importance of distinguishing between stressor (the challenge) and stress (the organism’s response).
Group B recommended that stress be defined as:
Any environmental influence that when processed by the individual leads to the experience of demand exceeding the resources of the individual and resulting in adverse effects on growth, development, and subsequent health.
The group suggested that because physiological responses to stress can vary with the environment, the Study might need to assess psychosocial stress at home and during childcare or school.
Objective 2: Itemize and Discuss Mechanisms of Stress Effects on Fetal Development and Early Childhood
David Ivor Wyn Phillips, Ph.D., F.R.C.P., Medical Research Council, Southampton General Hospital, presented two models (prenatal and postnatal) to facilitate discussion on the mechanisms of stress for the fetus, neonate, infant, and young child. In the first model, stress operates through the following postnatal mechanisms:
- Activation of neural systems
- Exogenous stimulation of the sympathetic nervous system and HPA axis
- Elicitation of reactive or defensive responses in the individual by external stressors
- Modulation of reactive responses to stress by individual differences.
A second model considered the interaction of mother, placenta, and fetus as a more complex set of interrelated prenatal processes:
- External factors affect maternal psychological and physiological internal states.
- Influences on the mother include maternal illness genes, early environment, transgenerational factors, physical factors, psychosocial factors, diet/nutrition, drugs, toxins, and smoking.
- Maternal responses to these influences affect nutrient levels, oxygen levels, hormones, and immune responses to the placenta. Maternal factors affect placental growth and differentiation.
- Placental hormones such as CRH feed back to the mother.
- Placental growth and differentiation affect nutrient levels, oxygen levels, hormones, and immune responses to the fetus.
- Fetal growth factors and hormones feed back to the placenta.
- Physical activity of the fetus feeds back to the mother.
- Genetic factors influence both fetal and placental responses.
- Maternal and placental states have systemic effects on the fetus, affecting the cardiovascular system, metabolism, central nervous system, and endocrine system.
Objective 3: Define and Select Exposure Measures
Janet DiPietro, Ph.D., Department of Populations and Family Health Sciences, Johns Hopkins University, explained to the group that defining and selecting measures of stress exposure could be organized into a framework based on cost and level of effort. Subjective measures of stress are generally not good predictors of physiological responses, which are subject to gene-environment interactions. However, subjective information such as that gathered in questionnaires can be correlated and validated with objectives measures. To measure exposure to psychosocial stressors, Group B recommended the following:
1. Paper-and-pencil questionnaires to assess maternal psychological functioning, including anxiety, pregnancy-specific issues, perceived stress, depression, and adult attachment
2. Paper-and-pencil questionnaires to assess catastrophic (natural disasters such as earthquakes, hurricanes, fires) and life events (death of a relative) as psychosocial stressors
3. Maternal physiologic indicators: cortisol (from saliva)/CRH (from blood, catecholamines, sex steroids (estrogens, testosterone), glucose (glycemic hemoglobin) challenge (50-g load), blood pressure, cardiac rate, polymorphisms, and banked amniotic fluid (from amniocentesis)
4. Other sources of maternal physiological activation (maternal occupation, maternal report of physical exercise, and maternal report of work exertion)
5. Indirect effects of maternal response to psychosocial stressors (nutrition and self-medicating activities)
6. Maternal-fetal-placental unit (placenta, cord blood, uterine and umbilical blood flow, fetal growth rate, and obstetric indicators of physiologic stress to fetus such as preeclampsia, restricted growth, preterm labor, steroid administration, etc.)
7. Infant exposures including arterial cord blood (cortisol levels, white blood cells counts, sex steroids concentrations), neonatal blood (PKU, heel stick sample cortisol/DHEA ratio), banked blood of infants in neonatal intensive care unit (NICU), banked breast milk.
Dr. DiPietro explained that because most fetal exposures are on the maternal side, fetal specimens of hair, nails, and meconium might serve as objective biomarkers of maternal behaviors such as self-medication and may reflect exposure to toxins such as pesticides and heavy metals. A group member noted that retinal vessel branching patterns may serve as biomarkers of fetal toxin exposure.
Objective 4: Define and Select Response Measures
The group decided that beyond the usual measures of body weight and length at birth, detailed pregnancy outcome measures might include:
- Body composition (compartmentalization of fat, muscle, bone, etc.)
- Anthropometric characteristics such as bone length (for example, femur) and abdominal circumference
- Facial configuration
- Retinal vasculature patterns
- Finger print/hand print patterns
- Digit ratios.
To measure responses to psychosocial stressors, Group B recommended the following:
- Pregnancy indicators such as prematurity, birth weight, and growth restriction
- Fetal indicators (heart rate and variability)
- Neonatal indicators including cranial ultrasound, gestational age/neuromaturation assessment, and a neurological exam
- Preterm infants (salivary or blood cortisol, vital signs, effects of beta-methasone, and neurological exam)
- Infancy indicators (growth and feeding, cardiac patterns, cognition and development)
- Infant stress response protocol including well baby exam, salivary cortisol, maternal report of infant temperament, observer rating of infant temperament, and maternal responsiveness.
Group members agreed that there is a need for standardized equipment and measures for fetal indicators.
Recommendations for Pilot Studies
- Evaluation of the use of skin patches to monitor cortisol levels and other biomarkers
- Assessment of diurnal variations in human stress responses
- Assessment of fetal blood cortisol-to-DHEA ratios
- Use of fetal retinal blood vessel patterning as indicator of exposure to environmental toxins
- Evaluations to develop standardized equipment and measures for fetal indicators
- Assess feasibility of using cranial ultrasound to assess fetal brain development
- Evaluate methodology for infant recognition memory/response to novelty, visual versus tactile assessments
- Evaluate use of Mullins assessment tool for infant cognition and development.
Conclusion
Dr. Klebanoff requested that each roup submit summaries of their discussions, definitions, and evidence by December 10, 2003. Each group’s summaries should list recommended measures and potential tools, provide references and rationales, and address issues such as timing and cost. The measures and tools should ideally have validity in a wide range of populations.
Participants
Christine A. Bachrach, Ph.D., NICHD, NIH, DHHS
Adelaide Barnes, NICHD, NIH, DHHS
Mary C. Blehar, Ph.D., National Institute of Mental Health, NIH, DHHS
William M. Callaghan, M.D., P.P.H., National Center for Chronic Disease Prevention and Health Promotion, CDC, DHHS
Evangelia Charmandari, M.D., M.S., NICHD, NIH, DHHS
Jennifer F. Culhane, Ph.D., M.P.H., Thomas Jefferson University
Christyn Dolbier, Ph.D., East Carolina University
Donald J. Dudley, M.D., University of Texas Health Science Center at San Antonio
Gary D. Hankins, M.D., University of Texas Medical Branch
Calvin J. Hobel, M.D., Cedars Sinai Medical Center, University of California, Los Angeles
Mark A. Klebanoff, M.D., M.P.H., NICHD, NIH, DHHS
Sarah S. Knox, Ph.D., NICHD, NIH, DHHS
Danuta Krotoski, Ph.D., NICHD, NIH, DHHS
Marci Lobel, Ph.D., State University of New York, Stony Brook
Catherine Monk, Ph.D., Columbia University
Virginia A. Rauh, Sc.D., Mailman School of Public Health, Columbia University
Uma M. Reddy, M.D., M.P.H., NICHD, NIH, DHHS
Sylvie Tordjman, M.D., Ph.D., Hopital Pitie-Salpetriere
Katherine Wisner, M.D., M.S., University of Pittsburgh Medical Center
Marilee C. Allen, M.D., School of Medicine, Johns Hopkins University Medical Institutions
Christopher Coe, Ph.D., University of Wisconsin
Janet DiPietro, Ph.D., Johns Hopkins University Bloomberg School of Public Health
William P. Fifer, Ph.D., Columbia University
Vivette Glover, Ph.D., D.S.C., Imperial College London
Carolyn Granier-Deferre, Ph.D., Universite Rene Descartes
Megan B. Gunnar, Ph.D., University of Minnesota
Peter W. Nathanielsz, M.D., Ph.D., Sc.D., New York University School of Medicine
David Ivor Wyn Phillips, Ph.D., F.R.C.P., Southampton General Hospital
Jeanne Ruiz, Ph.D., University of Texas Health Science Center at San Antonio
Curt Sandman, Ph.D., University of California, Irvine
Bea R. H. Van den Bergh, Ph.D., University of Leuven
Gerard H. A. Visser, M.D., Ph.D., University Medical Center Utrecht
Marian Willinger, Ph.D., NICHD, NIH, DHHS
Rosalind J. Wright, M.D., M.P.H., Harvard University Medical School