Prenatal Stress and Fetal Hemodynamics: a Systematic Review Terri Levine Professor Fiona Alderdice Professor Ruth Grunau Professor Fionnuala McAuliffe

Prenatal Stress Psychological distress experienced during pregnancy Distinct from anxiety experienced at other times Influenced by many factors life events, ethnicity, social support, income level, educational background, attitudes towards pregnancy, partner relationship Gurung et al. 2005. Psychosocial predictors of prenatal anxiety. Journal of Social and Clinical Psychology.

Prenatal Stress Assessed with self-reports and biomarkers in saliva, plasma, urine, hair Associated with stillbirth, preterm birth, lower fetal weight delayed neurodevelopment altered innate and adaptive immune responses “difficult” infant temperament emotional and behavioural problems lower academic achievement Dole et al. 2003. Maternal stress and preterm birth. American Journal of Epidemiology Rondo et al. 2003. Maternal psychological stress and distress as predictors of low birth weight, prematurity, and intrauterine growth restriction. European Journal of Clinical Nutrition Sandman et al. 2012. Exposure to prenatal psychobiological stress exerts programming influences on the mother and her fetus. Neuroendocrinology

Pregnancy-Specific Stress Fears and concerns related to pregnancy Fetal health, diet, weight gain, appearance, labour, delivery May be more sensitive predictor of outcomes than general prenatal stress fetal behaviour, infant cognitive/motor development, emotional regulation Associated with shorter gestation, preterm birth, delayed neurodevelopment, decreased grey matter, delayed executive function Alderdice and Lynn. 2011. Factor structure of the prenatal distress questionnaire. Midwifery Davis and Sandman. 2010. The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development. Child Development

Prenatal Stress and Fetal Hemodynamics Relationship between maternal psychological state and fetal blood flow relatively unexplored Significant hemodynamic changes occur during pregnancy to meet the needs of the developing fetus

Doppler Ultrasound Non-invasive measurement of placental blood flow Gathers information about maternal and fetal blood flow Insonates: Maternal uterine arteries Fetal umbilical artery Fetal middle cerebral artery Fetal venous circulation Transabdominal Fetal Ultrasound Ultrasound Transducer Sound waves Fetus Placenta Uterus

Doppler Ultrasound Poor placentation results in resistance to blood flow Decreased uterine artery blood flow linked to pre-eclampsia and fetal growth restriction Decreased umbilical artery blood flow linked to fetal growth restriction, fetal distress, NICU admission, worse neurodevelopmental outcomes

Aims Studies assessing link between prenatal stress and fetal well-being have not been systematically reviewed Examine relationship between prenatal stress and abnormal fetal hemodynamics measured by Doppler ultrasound

Methods: Study Criteria Eligibility criteria: measured resistance, pulsatility index, and/or systolic/diastolic ratio in the uterine, umbilical, and/or fetal middle cerebral artery using Doppler ultrasound measured prenatal stress with ≥1 standardised measure Ineligibility criteria: study participants not human study methodology inadequately described full English text not available

Methods: Search Strategy Dates: All studies published through April 2014 Databases: Medline Embase PsycINFO Maternity and Infant Care CINAHL Search terms: pregnancy; stress; blood; fetus; Doppler; ultrasound

Methods: Data Extraction Specifically designed data-extraction form Authors Year of publication Location of study Gestational age(s) at assessment Exclusion criteria Measures used Results Limitations

Methods: Quality Analysis Standardised outline for assessing evidence quality 6 areas of potential bias: Study participation Attrition Prognostic factor measurement Outcome measurement Confounding factor analysis Data analysis

Results: Included Studies 2101 records identified in database search 1733 records screened after duplicate removal 1609 studies excluded by title 124 abstracts screened 112 studies excluded by abstract 11 full-text studies assessed for eligibility 11 studies included

Results: Uterine Artery Blood Flow 9 studies 2 with significant results Significant association between state and trait anxiety scores and reduced blood flow (Teixeira et al. 1999) Prenatal stress linked with reduced blood flow (Vythilingum et al. 2010) 7 without significant results Harville et al. 2008, Helbig et al. 2011, 2013, Maina et al. 2008, Mendelson et al. 2011, Monk et al. 2011, Kent et al. 2002

Results: Umbilical Artery Blood Flow 9 studies 2 with significant results Reduced blood flow linked with prenatal stress and state anxiety scores (Caliskan et al. 2009) Women with high trait anxiety scores had reduced blood flow (Sjostrom et al. 1997) 7 without significant results Harville et al. 2008, Helbig et al. 2011, 2013, Maina et al. 2008, Mendelson et al. 2011, Monk et al. 2011, Vythilingum et al. 2010 Normal Abnormal

Fetal Middle Cerebral Artery Measure of “brain-sparing” phenomenon 2 studies 1 with significant results Fetal brain circulation was favoured in women with high trait anxiety (Sjostrom et al. 1997) Indicates a pathological redistribution of blood flow 1 without significant results Vythilingum et al. 2010

Strengths of Included Studies Thoroughly described population groups Adequately described prognostic factors and outcome measurement Standardised outcome measures decrease measurement bias simplify study comparisons

Limitations of Included Studies Small sample sizes 6 cross-sectional acute v. chronic stress changes in blood flow over time Choice of stress measure(s) varied Only 1 measured pregnancy-specific stress

Limitations of Included Studies None adequately explained study attrition 5 excluded participants with psychiatric diagnoses, 6 did not Specific exclusion criteria differed Only one measured stress biomarkers

Sample Study Largest sample size: 872 Two assessment periods ~17 and ~27 weeks Biomarker analysis Cortisol in saliva and CRH in blood Good attention to confounding factors Age, education, marital status, etc. Staggered Doppler ultrasound, biomarker analysis, stress measures

Future Studies Larger sample sizes Repeated assessments across gestation Biomarker analysis Better control for confounding factors Better accounting for psychiatric illness and medication use Measures of pregnancy-specific stress

Conclusions High levels of stress during pregnancy pose a risk to maternal and infant health Underlying mechanisms remain unclear Relationship between prenatal stress and fetal hemodynamics merits additional investigation Systematic review findings inconclusive but interesting Attention to mental health during pregnancy essential Lobel and Dunkel Schetter. 2014. Pregnancy and prenatal stress. Encyclopedia of Mental Health, Second Edition, in press.

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