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Doi:10.1016/j.neubiorev.2004.10.007

Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review Bea R.H. Van den Bergha,*, Eduard J.H. Mulderb, Maarten Mennesa,c, Vivette Gloverd aDepartment of Developmental Psychology, Catholic University of Leuven (KULeuven), Tiensestraat 102, 3000 Leuven, Belgium bDepartment of Perinatology and Gynaecology, University Medical Center Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands cDepartment of Paediatric Neurology, University Hospital Leuven (KULeuven), Herestraat 49, 3000 Leuven, Belgium dInstitute of Reproductive and Developmental Biology, Imperial College London. Du Cane Road, London W12 0NN, UK A direct link between antenatal maternal mood and fetal behaviour, as observed by ultrasound from 27 to 28 weeks of gestation onwards, is well established. Moreover, 14 independent prospective studies have shown a link between antenatal maternal anxiety/stress and cognitive,behavioural, and emotional problems in the child. This link generally persisted after controlling for post-natal maternal mood and otherrelevant confounders in the pre- and post-natal periods. Although some inconsistencies remain, the results in general support a fetalprogramming hypothesis. Several gestational ages have been reported to be vulnerable to the long-term effects of antenatal anxiety/stress anddifferent mechanisms are likely to operate at different stages. Possible underlying mechanisms are just starting to be explored. Cortisolappears to cross the placenta and thus may affect the fetus and disturb ongoing developmental processes. The development of the HPA-axis,limbic system, and the prefrontal cortex are likely to be affected by antenatal maternal stress and anxiety. The magnitude of the long-termeffects of antenatal maternal anxiety/stress on the child is substantial. Programs to reduce maternal stress in pregnancy are thereforewarranted.
q 2005 Published by Elsevier Ltd.
Keywords: Pregnancy; Stress; Programming; Cortisol; Fetal behaviour; Child behaviour; Developmental neuroscience; Review 2.2. Antenatal maternal stress and anxiety and fetal behaviour on ultrasound observation . . . . . . . . . . . . . .
3. The short and long term links between anxiety/stress during pregnancy and the development of the child . . . . . . . .
* Corresponding author. Tel.: C32 16 32 58 60; fax: C32 16 32 60 55.
E-mail address: [email protected] (B.R.H. Van 0149-7634/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.neubiorev.2004.10.007 B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 3.5. Effects of antenatal maternal depression, a co-morbid symptom of anxiety . . . . . . . . . . . . . . . . . .
3.6. Effects of antenatal anxiety/stress on handedness . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Two physiological mechanisms by which the maternal affective state may affect the fetus in humans . . . . . . . . . .
5. Stress hormones and the developing fetal nervous system: how are they related to behavioural/emotional regulation neurotransmitter systems, and disturbed behaviour inanimal offspring A consistent finding in the non-human primate work is that stressing the mother during ‘And surely we are all out of the computation of our age, pregnancy has a long-term adverse effect on attention span, and every man is some months elder than he bethinks him; neuromotor behaviour, and adaptiveness in novel and stress- for we live, move, have a being, and are subject to the inducing situations (e.g. enhanced anxiety) of the offspring actions of the elements, and the malices of diseases, in that other World, the truest Microcosm, the Womb of our Human studies on the long-term effects of prenatal stress Mother'(Sir Thomas Browne, Religio Medici, 1642) are difficult. In 1893, Dr Alfred W. Wallace (cited in )wrote to Nature: ‘Changes in mode of life and in intellectual The question of the importance of prenatal environmen- occupation are so frequent among all classes, that materials tal factors for development, behaviour and health, has been must exist for determining whether such changes during the scientifically studied from the 1940s onwards in humans prenatal period have any influence on the character of the and even earlier, from the 19th century onwards, in offspring' (p. 3). Joffe concluded that, in human experimental embryology (see The fetal program- studies, obtaining sufficient control of genetic and post-natal ming hypothesis states that the environment in utero can environmental factors had been the major difficulty to alter the development of the fetus during particular sensitive enable the post-natal behavioural differences under inves- periods, with a permanent effect on the phenotype. In recent tigation to be attributed conclusively to prenatal variables.
years, the work of Barker has given a great impetus to However, he concluded that even if uncertainty about research in this particular field. He proposed "the fetal etiological relationships exists, human studies provide origins of adult disease hypothesis". This states that the sufficient evidence to enable preventive action to be physiological, neuroendocrine or metabolic adaptations that initiated with regard to a variety of childhood disorders, enable the fetus to adapt to changes in the early life without waiting for the methodological issues to be environment result in a permanent programming (or re- unraveled. ‘though the action may be more effective programming) of the developmental pattern of proliferation when they are' p. 308).
and differentiation events within key tissues and organ In humans, studies during the last two decades have systems and can have pathological consequences in later life provided continuing and mounting evidence that negative The key observation on which this was based was that maternal emotions during pregnancy are associated with an weight at birth was a strong risk factor for coronary heart adverse pregnancy outcome. The association between high disease, diabetes mellitus, and obesity later in life. This antenatal anxiety/stress and preterm delivery and low birth finding has been reproduced in many independent studies, weight for gestational age are the most replicated findings although it appears to be the ponderal index rather than birth and have been discussed fully elsewhere (for recent reviews weight that matters (for reviews see for coronary heart see A meta-analysis of 29 studies on work- disease; for obesity). Most of the work on the possible related stress and adverse pregnancy outcome showed that mechanisms underlying these findings have focused on occupational exposures significantly associated with pre- nutrition, although there is also evidence that the hypo- term birth included physically demanding work, prolonged thalamic–pituitary–adrenal (HPA)-axis may be involved standing, shift and night work, and a high cumulative work In parallel with this work in humans there has been a fatigue score. Physically demanding work was also related strong body of animal research linking prenatal stress and to pregnancy-induced hypertension and preeclampsia .
Pregnancy-induced hypertension was shown to be related to B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 Trait Anxiety score (and maternal ponderal index) during the 7th month of pregnancy Hypertension and Criteria to define episodes of each of four fetal behavioural states preeclampsia in turn, increase the rate of preterm delivery Behavioural state and small-for-gestational-age infants Hansen et al.
have shown that severe life events during pregnancy Heart rate pattern increased the frequency of cranial–neural-crest malfor- mations in the child. Unexpected death of a child during the first trimester was associated with adjusted odds ratios of 8.4 (2.4–29.0) for cranial–neural-crest malformations and 3.6 States 1F and 2F are also called quiet sleep and active sleep, respectively; (1.3–10.3) for other malformations.
states 3F and 4F, quiet wakefulness and active wakefulness, respectively In this paper, we review studies of the past two decades, a HRP A is a stable heart rate with a narrow oscillation bandwidth; HRP concurrently or prospectively studying the link between B has a wider oscillation bandwidth with frequent accelerations during antenatal maternal anxiety/stress on the one hand, and fetal movements; HRP C is stable (no accelerations), but with a wider oscillation behaviour and later development of the child on the other bandwidth than HRP A; HRP D is unstable, with large, long-lasting hand. Evidence for underlying physiological mechanisms in accelerations that are frequently fused into sustained tachycardia. If none of humans and possible effects of stress hormones on prenatal these combinations are met this is called no-coincidence (NoC) orindeterminate state.
brain development are also reviewed. More specifically, thequestion is raised whether maternal anxiety, apart fromaffecting the HPA-axis and limbic system may alsoaffect the development of the prefrontal cortex, which is characterize stable temporal organisation near term presumed to underlie behavioural alterations seen in Four distinct fetal states can be identified based on children of mothers who were highly anxious/stressed specific associations between the three variables mentioned during pregnancy. Finally, we formulate some suggestions (see legend to for descriptions). Although some for strengthening further research.
level of temporal organization is already present at 28–30weeks, behavioural state organization progressively devel-ops between 30 and 40 weeks, both in utero and in low-risk 2. Antenatal maternal stress and anxiety preterm born infants This developmental pattern, and the human fetus which parallels particular aspects of brain development, ischaracterized by a gradual increase in quiet sleep and awake Reports from the pre-ultrasound era, both anecdotal and states, and a profound decrease in indeterminate state, a semi-scientific (i.e. non-controlled), have suggested that gradual decrease over time in body movements and basal prenatal maternal stress, anxiety, and emotions affect fetal FHR, and an increase in FHR variability and fetal move- functioning, as evidenced by increased fetal heart rate ment-FHR coupling (i.e. FHR accelerations associated with (FHR) and motility Ultrasound techniques, enabling body movements) Besides macro-analysis of FHR monitoring and direct fetal behaviour observation for behavioural state organization, i.e. calculation of the % of prolonged periods of time, have for two decades been used time spent in each state, basal FHR, its variability, and the % in longitudinal and cross-sectional studies of the effects of incidence of body movements during episodes of states 1F antenatal maternal anxiety and stress. Both observational and 2F (see are often calculated (micro-analysis) to and stress/emotion-induced study designs have been identify state-specific characteristics.
employed and the results will be reviewed here. The results Fetal behavioural states can be regarded as precursors of can only be understood in the context of some background the adult sleep–wake states. Fetal and adult sleep states not information on normal fetal neurobehavioural development only share comparable features of non-REM/REM, cardi- ovascular, respiratory, and (probably) metabolic control, butalso share the neuronal substrate, neurotransmitters, and 2.1. Normal development of human fetal behaviour receptors that are believed to underlie sleep control fromearly in fetal life onward A number of distinct fetal movement patterns has been Recent studies on adult animals and humans have distinguished, emerging at a well described time point elucidated that the cyclic alternation between non- during the first 15 weeks of gestation (post-menstrual age), REM/REM states and wakefulness is a highly regulated including body movements, breathing movements, hiccups, and arm, leg, head, and mouth movements As Several neuronal networks involving distinct mesopon- pregnancy progresses, rest–activity cycles become increas- tine and hypothalamic brain areas and a variety of excitatory ingly linked to specific fetal heart rate patterns and to and inhibitory neurotransmitters, -modulators, and -peptides absence and presence of rapid eye movements (REM), have been found to form an intricate web of interactions respectively. These cycles finally develop into ultradian underlying sleep–wake control (for detailed reviews see fetal behavioural states (sleep–wake cycles), which Each behavioural state is now believed to result B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 from a specific balance between activities of wake- macro- and/or micro-analyses for recordings that lasted at promoting and sleep-promoting neurons and the activities of many neurotransmitter systems (cholinergic, noradren- Three studies that have evaluated the immediate ergic, serotonergic, GABA-ergic).
relationship between maternal anxiety/stress and fetal Processes during sleep have been found to be intimately behaviour in the first half of pregnancy found no related to memory and cognition in adult awake state observable effect on spontaneous motor activity (nos. 10– Disturbed sleep–wake organization is a characteristic of 12). Four out of the five independent studies with a neurological and psychopathological diseases (e.g. ADHD, comparable study design (nos. 2–4, 9, 11) have reported autism, depression, schizophrenia). At least for some of these, evidence of increased arousal in near-term fetuses of high exposure to prenatal maternal stress has been suggested as a stress/anxious women, as reflected by an increase in fetal causative factor. The sleep and stress control systems share wakefulness, increased FHR variability and % of body particular brain loci, such as the locus coeruleus and forebrain movements during active (REM) sleep and state 4F, and a centres. This brings us to the question of whether there are decrease in the amount of quiet (non-REM) sleep. The observable, objective effects of gestational stress on the results of DiPietro et al. can be generally viewed to be in developing human fetus. If so, which features of fetal accordance with these findings, although no information is behavioural development and organization are being affected, provided as to which fetal functional aspect was specifi- cally involved. In two studies (nos. 7, 8) they showed there differential effects on the fetus between different types of overall increased % of body movements and FHR maternal stress, and which mechanisms may be involved? variability and accelerations (at 36 weeks in particular) infetuses whose mothers reported higher levels of perceived 2.2. Antenatal maternal stress and anxiety and fetal stress and emotions, more pregnancy-related hassles, and a behaviour on ultrasound observation negative valence toward pregnancy. Results from earlierreports (nos. 5, 6), i.e. reduced FHR variability and poorer An overview of the results obtained in 12 observational movement-FHR coupling in fetuses of women with high studies on the relationship between prenatal maternal perceived stress, seem to be different from the later psychological states and fetal behavioural development is findings of this group. Of particular interest are the presented in All studies involved uncomplicated observations that fetuses of women with a positive vs.
pregnancies, and healthy pregnant women (mainly nullipar- negative attitude toward pregnancy exhibit different overall ous) and their newborns. The studies were also uniform levels of motor activity (reduced versus increased, regarding the demographic background of the participants, respectively). As positive (pleasant) emotions and negative the majority being Caucasian, well-educated, and of middle stressors are believed to have similar physiological effects SES-class. Maternal age, the number of participants, and (on the fetus), their observations deserve to be replicated in fetal recording length on the other hand, varied largely other studies.
among the studies. Most studies controlled for the possible The findings for maternal anxiety/stress on fetal effect of circadian rhythms and meals, and some also performance are in line with the well-known report on adjusted for potential confounders, including maternal age,SES, smoking, and alcohol intake. The levels of maternal hyperkinetic fetuses of acutely stressed women during an anxiety and stress were assessed by using self-administered earthquake (no. 1), but are opposite to those described by questionnaires, which are either widely used and validated Groome et al. for unknown reasons (no. 4). Their sample or developed by the authors. The Spielberger State Trait consisted for nearly 50% of black women, and fetuses of Anxiety Inventory (STAI was used most frequently black women have been described to spend more time in among the studies. It differentiates between current feelings quiet sleep than white fetuses As these data were not of tension and apprehension (state anxiety) and an analysed by race, it remains unclear whether this con- individual's relatively stable anxiety-proneness (trait founder was a factor of importance with respect to the anxiety). Some studies used measures of general stress, mentioned discrepancy in findings.
involving either stress-provoking (daily hassles, life events) One study has reported that stress experienced in early or stress-resulting aspects (stress appraisal, perceived pregnancy had an observable effect on fetal behaviour as stress). Pregnancy-specific anxiety and affect were included early as at 28 weeks (no. 11). Only a few studies have in two studies (nos. 7, 8; ). Similar definitions of fetal focused explicitly upon the timing of gestational stress (nos.
movement patterns and behavioural organization (when 3, 11). They have suggested that maternal anxiety/stress appropriate) were used across the studies, and fetal move- experienced during early pregnancy, but also during later ments were observed and registered by a researcher, except stages of pregnancy, are associated with the above- for the studies by DiPietro et al. (nos. 5–8). These authors mentioned fetal effects near term. The latter results suggest used an ultrasound device for automated detection of fetal that maternal anxiety/stress-related mechanisms might motility (actograph) and analysed the 50-min records for affect the fetal nervous system during the first two trimesters total observation time only. Other groups provided results of of pregnancy. However, possible alterations have only been Table 2Ultrasound studies of the effect of prenatal maternal stress and anxiety on fetal behaviour Ianniruberto 1981 Qualitative description: "panic stricken" Fetal hyperkinesia for 2–8 h, followed women during earthquake by a 24–72 h period of reduced motility GA: 18–36 wkRL:– Positive correlation between state Administered on day of recording anxiety and %FM (during total rec. time Age: 26 (19–31) yr and during S2F-4F); No effect of induced maternal emotions Negative correlation between state anx.
Nulliparous: 100% State scale administered on day of (T3) and trait anx. (T1,T2,T3) and Age: 24 (20–28) yr State and Trait scales at 12–22 wk (T1) Positive correlation between state anx.
23–31 (T2) and 32–40 wk (T3) and %S4F and %FM (during total rec.
time and during states 2F-4F) Positive correlation between state and Administered 3 days before fetal trait anx. and %S1F; Negative correlation between state and trait anx. and %FM during state 2F Daily hassles (general) and uplifts Greater perceived stress was associated expressed as one score (ratio) of FHR: mean FHR and variability (SD) with reduced FHR variability; age: 29 (22–36) yr perceived stress/stress appraisal; infor- GA: 20–40 wk, 6 times at 4–wk interval No reported effects on %FM and % state mation over past 24 h RL: 50 min/session Daily hassles (general) and uplifts Higher reported stress was associated expressed as one score (ratio) of FHR: baseline FHR FHR-FM coupling with less FHR-FM coupling Age: 29 (22–36) yr perceived stress/stress appraisal; infor- GA: 20–40 wk, 6 times at 4–wk interval mation over past 24 h RL: 50 min/session (1) intensity of experienced emotions Increased %FM and tendency toward FHR: # accelerations more FHR accelerations in women who (2) daily (general) stressors (perceived GA: 24, 30, 36 wk were more hassled or negative about RL: 50 min/session their pregnancy (higher intensity of (3) pregnancy-specific daily hassles and hassles relative to uplifts) and who uplifts (frequency, intensity, ratio has- reported more daily stressors;decreased %FM in women with high emotional (4) composite Z-score intensity, but only for women in low-SES class (continued on next page) Table 2 (continued) (1) intensity of experienced emotions Decreased FHR at 36 wk in women who FHR: mean FHR and variability (SD) showed high emotional intensity; Age: 30 (21–39) yr (2) daily (general) stressors (perceived GA: 24, 30, 36 wk Increased FHR variability at 36 wk in RL: 50 min/session women who had higher frequency of (3) pregnancy-specific daily hassles and uplifts (frequency, intensity, ratio has- Increased %FM in women who reported greater emotional intensity, appraised (4) composite Z-score their daily lives as more stressful, and who had more pregnancy-specific has-sles and a more negative valence toward pregnancy;Decreased %FM in women who per- ceived their pregnancy to be more intensely and frequently uplifting andwho had a positive emotional valencetoward pregnancy Sjo¨stro¨m 2002 High anxiety group: tendency toward Nulliparous: 100% Administered about 2 wk before fetal FHR: basal FHR and variability (esti- more %HRP-C (state anx.) and %HRP- Age: 26 (SD 4) yr recording; the state anx. scale was mated from paper chart) Median split analysis D (state and trait anx.); tendency toward considered to reflect perceived anxiety lower FHR variability in episodes of between 25 and 36 wk HRPs A and B (state anx.); lower FHRin HRP-C and increased FHR variability in HRP-D (state and trait anx.); positive correlation between state/trait anx. and %HRP-D;No effect of anxiety on %FM in each ofthe distinct fetal states No significant relationships between Administered on day of recording state or trait anxiety and %FM or other fetal movement patterns STAI: state anx. scale before fetal FM: observer (T1–T3) High numbers of LE and DH reported at Nulliparous: 100% recording;Life events (LE) and daily FHR: basal FHR and FHR variab.
T1 were not related to %FM at T1, but Age: 31 (17–45) yr hassles (DH): frequencies reported over were sign. associated with increased GA: 15–17 wk, 27–28 wk, 37–39 wk Analysis: high-low con- %FM and FHR variability during Administered at 15–17wk (T1), RL: 60 min (T1, T2) and 120 min (T3) trasts (scores OP75 vs ! episodes of HRP-B (S2F) at both T2 and 27–28 wk (T2), and 37–39 wk (T3) P25) and correlational T3, and, at T3, with an increase in%HRP-D (%S4F), a decrease in %HRP-A (%S1F) and a decrease in %NoC;Fetuses of high-stress women exhibitedbetter state organization;No sign. effects of state/trait anxiety atT1–T3 on the near-term fetus Self-constructed questionnaire adminis- FM: arm, leg, head movements No relationship between maternal stress Low-risk population tered just before fetal observation scores and the numbers of fetal arm, leg, and head movements –information not provided or not applicable (e.g. FHR at early gestation, !24 wk); %FM: incidence of fetal (gross) body movements, expressed as % of time; FHR: fetal heart rate; HRP: fetal heart rate pattern; S1F-4F:fetal behavioural states 1F through 4F; %NoC: incidence of no-coincidence of state parameters (% of time); GA: gestational age; RL: record length; micro: micro-analysis of %FM and/or FHR and its variability duringepisodes of HRPs A–D or states 1F–4F.
B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 observed so far with ultrasound from 28 weeks of gestation 3. The short and long term links between anxiety/stress during pregnancy and the development of the child A number of studies have recently investigated the effects of induced maternal stress, emotions, and hormonal 3.1. Overview of results changes on fetal functioning Changes in fetal heartrate and motility that occurred during a maternal cognitive Evidence from earlier studies has been largely incon- challenge (arithmetic test or the Stroop colour-word clusive but more recent methodologically improved matching test) were compared with values obtained during studies support the notion of an overall relationship pre and post-test periods. The whole procedure was between negative maternal emotions during pregnancy completed within about 15 min. The observed effects during and reproductive outcome . The intensity and chronicity testing compared with baseline were usually statistically (or duration) of antenatal anxiety/stress and lack of significant but small, e.g. a 10% decrease in fetal movement appropriate coping mechanisms have been identified as and a 5 bpm increase in fetal heart rate .
critical factors A recent review suggests that The results of this kind of experiments are clearly of antenatal maternal stress results in a general susceptibilityto psychopathology .
interest but have to be viewed with some caution because We here review published or ‘in press' prospective of potential methodological pitfalls. As pointed out above, studies from the past 20 years, in which the assessment of the human fetus exhibits a large amount of spontaneous maternal anxiety/stress was started during pregnancy body movements occurring at a rate of about 0.4–5 per (The 17 studies-14 independent, one two-wave min . Body movements are associated with FHR study (nos. 11, 14), and one three-wave study (nos. 6, 16, accelerations, such that it may increase from 130 to 160– 17)—all with a different design are summarized. Studies are 170 bpm within a few seconds. Finally, fetal behaviour is ordered by the age of the child at final assessment.
organized in rest–activity or sleep–wake cycles. Both In general, the studies show that antenatal maternal physiological variables and responsiveness to external anxiety/stress was positively related to regulation problems stimuli depend on the state the fetus is in (input–output at the cognitive, behavioural, and emotional levels. These state relationship). Thus, for successful testing fetal problems were assessed either by behavioural observations responses to elicited maternal psychological challenges, or recordings (nos. 1–6, 8–10, 16, 17), and/or by teachers' stimulus-free control periods of the same duration as that ratings (nos. 13, 15, 16), and/or by mother's ratings (nos. 4, of the test procedure are required. These control periods 6–8, 11–16).
must be obtained from the same fetus during a In newborn babies, regulation problems were expressed comparable behavioural state In the only controlled in less good scores for the Brazelton Neonatal Assessment (counterbalanced) study in this field to date (no. 2), the Scale (nos. 1, 9), neurological examination (no. 2), cardiac effect of induced emotion on fetal performance was vagal tone (no. 3) and behavioral states (no. 6).
studied by showing a film of a normal delivery to Infants were rated by an observer as having less good pregnant women at term during the second half hour of a interactions with their mother (no. 4), being highly reactive 2-h fetal behaviour recording. Although this film evoked (no. 5), worse regulation of attention (no. 8) and having intense maternal emotions (some women were crying poorer language abilities (no. 10), and by their mother as when watching) and a positive correlation was found having sleeping, feeding and activity problems (no. 6), and between maternal state anxiety and fetal body movements, being irritable and difficult (nos. 6–8). Scores on the Bayley no differences in movement incidence and behavioural Scales of Infant Development were worse at 8 and 24 m state distribution were revealed when comparing data of (nos. 8–10), but not at 7 m (no. 6).
the experimental day with comparable data on a control Pre-school children and children were rated by their day when no maternal emotions were induced. Further mother (nos. 11–16), teachers (nos. 15, 16), an external understanding of immediate maternal–fetal interactions observer (no. 16) or themselves (no. 16) as showing poorer awaits future studies that take into account the attention, hyperactivity, behavioral and emotional pro- peculiarities of fetal behaviour.
blems, and they were rated by their teacher has having To conclude, a link between antenatal maternal mood low school grades and bad behaviour (no. 13).
and ultrasonographically observed fetal behaviour is well Finally, adolescents showed impulsive behaviour when established. Although two studies showed that maternal performing computerized cognitive tasks and scored anxiety/stress measured at 12–21 and 15–17 weeks lower on intelligence subtests (no. 17). Unpublishedresults of Obel et al. (personal communication, influenced near term fetal behaviour, an immediate link indicate that stressful life events increased the risk for has in general only been observed from 27 to 28 weeks of ADHD problems in pre-adolescents (9–11-year-olds).
pregnancy onwards. The mechanisms underlying these links Unpublished results of Van den Bergh et al. confirm are presently obscure.
a link between high antenatal anxiety and behavioural Table 3Prospective studies on the effect of prenatal maternal anxiety and stress on postnatal behavioural developmenta Anxiety/stress measure in preg- Outcome assessment: Statistical analyses: Impact of antenatal anxiety/stress: Size at outcome, characteristics of Child's age at outcome; gender; Method; confounders controlled Negative child outcome (normal Timing; questionnaires; physio- measures; observer letter); positive and zero effect !20 wk; 30–34 wk Higher total distress score associ- Age: 31 (18–40) yr Total distress score based on: Trier Neonatal Behavior Assessment Controlled for: gestational age ated with more infant regulation No obstetrical or psychiatric path- Inventory for the Assessment of (NBAS), by observer (Medical record data on birth) problems on NBAS (e.g. alertness, Chronic Stress, Prenatal Distress cost of attention, state regu- Singleton pregnancy Questionnaire, Perceived Stress Higher basal cortisol levels at Life Experience Scale 30–34 wk related to more infant Morning cortisol: saliva samples difficulties in habituating to new or ! 20 wk, 30–34 wk Linear and logistic regression Moderate to severe stress associ- 70 most stressed versus 50 non- Questionnaire about life events, Controlled for: maternal age, ated with lower birth weight, stressed (from cohort) conditions at work (e.g., fatigue, Head circumference gestational age, educational level, smaller head circumference and chemicals), smoking, alcohol, Prechtl's neurological obser- social support, smoking, alcohol, lower Prechtl's neurological score vation, by external observer tranquillizers, gender of child Singleton pregnancy General Health Questionnaire (Prechtl's Obstetric Optimality %16 wk; 32–34 wk Birth, 1 day, 3–4 wk Correlations; regression Higher negative TE at %16 wk, Nulliparous: 100% Negative trait emotionality (TE) Medical record data (e.g. Apgar associated with higher neonate Age: 17.3 (13–19) yr based on: State Trait Anxiety 1', 5'; risk factors at birth and Apgar 50 and lower cardiac vagal No obstetrical risk or psychiatric Inventory (STAI)-trait, State Trait 24 h; no. of resuscitation methods Anger Scale (STAS)-trait, and Higher negative SE at 32–34 wk NEO-AC Personality Inventory Cardiac vagal tone at 3–4 wk (data associated with more abnormal- depression, anxiety and hostility analyzed from 100 infant resting ities on the newborn profile EKG according to Porges' Social support mediated effect Negative state emotionality (SE) between TE at %16 wk and based on: STAI-state, STAS-state, cardiac vagal tone Beck Depression Inventory (BDI) Higher cortisol at %16 wk Inventory of Socially Supportive associated with lower neonate Apgar 10, 50 and increased need for Saliva cortisol: 5 samples at resuscitation at birth 20 min intervals at No effect of SE at %16 wk, TE at 32 wk, cortisol at 32–34 wk onmeasurs of infant outcome orcardiac vagal tone High pregnancy risk index group Pregnancy risk index (scale of 100 face-to-face play interactions had high postnatal maternal scores Braverman and Roux on demo- (videotape), by external observer on BDI, STAI and Locus of No obstetrical risk graphic characteristics, stress, Colorado Child Temperament Inventory, by mother Depressed mothers have less opti-mal interactions (e.g. infant lessrelaxed, more fussiness, moredrowsy state) and rate their infantas being more emotional Correlations; hierarchical linear Higher antenatal anxiety and STAI-state anxiety 12 girls, 10 boys depression related to higher infant Age: 28 (18–36) yr Center for Epidemiological Harvard Infant Behavioral Reac- Controlled for: anxiety and negative behavioral reactivity No psychiatric risksingleton preg- Studies Depression Inventory tivity Protocol (videotape), by depression 8 wk after birth external observer (Medical record data on medicalrisk and birth) 12–22 wk; 23–31 wk; 32–40 wk Correlations; LISREL Higher antenatal state and trait Nulliparous: 100% Prechtl's neurological observation Controlled for: postnatal anxiety at anxiety related to: more activity in (Important Life Event Scale, Daily (1 wk) by external observer; 2 h state 2–4 and more crying at 1 wk; No obstetrical risk or psychiatric Hassles Scale, Coping Scale, behavioral state observation (Educational level, smoking, birth more difficult temperament at Social Support Scale, Pregnancy (1 wk) by observer weight for gestational age, gender 10 wk and 7 m; more irregularity Feeding score and mother-infant of child, Prechtl's Obstetric in feeding and sleeping, more interaction during feeding (1 wk; Optimality Score) activity at 7 m.
10 wk), by external observer No effect of anxiety on Prechtl's Behavioral ratings (1 wk; 7 m), neurological score, feeding score, ITQ (10 wk; 7 m), ICQ (7 m), by (Unpublished result: higher social BSID (7 m), by observer support and expression of emotions associated with higher infant MDI and PDI) Near 21 wk; 35 wk Mothers of infants with difficult Nulliparous: 100% ITQ-Revised, by mother temp. had higher STAI anxiety Personality Research Form scores at 21 and 35 wk, were more Self-esteem (Epstein scale) defendant and impulsive, have less self-esteem than mothers of infants with easy temp.
NZ35–100 (study 4) Correlations; t-tests Mothers of infants with difficult Institute for Personality Assess- ITQ-Revised, by mother (Maternal age, Apgar score, edu- temp. had higher IPAT-anxiety ment and Testing (IPAT) anxiety cation, parity, gender of infant, and less optimal CPI personality No obstetrical risk or psychiatric scale; California Personality length of labour, birth weight) scores during pregnancy than Inventory; (CPI); McGill Pain mothers of infants with easy temp.
Maternal characteristics correlated Cortisol, ACTH, b-endorphin: with b-endorphin from placental maternal and placental blood blood sample (only 4 of 120 tests samples at 26–34 wk, during early Mothers of difficult infants hadlower levels of b-endorphin during later stages of labor (only 1 of 15tests significant) (continued on next page) Table 3 (continued) Anxiety/stress measure in preg- Outcome assessment: Statistical analyses: Impact of antenatal anxiety/stress: Size at outcome, characteristics of Child's age at outcome; gender; Method; confounders controlled Negative child outcome (normal Timing; questionnaires; physio- measures; observer letter); positive and zero effect 15–17 wk; 27–28 wk; 37–38 wk 10 days; 3 m; 8 m Correlation; logistic regression; Higher fear of giving birth and Nulliparous: 100% 86 girls, 84 boys having handicapped child at Pregnancy Related Anxieties BSID and IBR (3 m, 8 m), by Controlled for: postnatal perceived 15–17 wk associated with more No obstetrical risk external observer stress and depression at 3 m, 8 m, Perceived Stress Scale ICQ (3 m, 8 m) by mother (total educational level, smoking, alco- problems at 3 and 8 m Singleton pregnancy (Trait Anxiety, depression score for adaptational problems hol use, gender, breastfeeding) Higher perceived stress at 15– and difficult behavior) (SES, birth weight, gestational age 17 wk associated with more diffi- Saliva cortisol: 7 samples every at birth, obstetric risk, GHQ) cult infant behavior at 3 m and 8 m 2 h starting at 8 a.m, at 15–17 wk, and infant attention-regulation 27–28 wk, 37–38 wk More daily hassles at 15–17 wkassociated with lower infant MDI Higher fear of giving birth at 27– 28 wk related to lower infant MDIand PDI at 8 mHigh early morning salivary cor-tisol at 37–38 wk associated with lower infant MDI at 3 m and PDI No effects of daily hassles onattention regulation and difficultbehavior c2; linear regression; Higher anxiety associated with 52 girls, 53 boys Controlled for: gender child, edu- lower score on orientation cluster Age: 30.4 (21–38) yr NBAS (3 wk), by observer cational level, birth weight, type of of NBAS at 3 wk and lower MDI No medical pathologysingleton BSID and IBR (1 and 2 yr), by feeding, parity, HOME-subscale, alcohol, smoking during preg- c2 (without control for confoun- nancy, postnatal maternal anxiety der); high anxiety associated with and depression symptoms lower scores on task orientationand motor co-ordination on the IBR at 12 m, and lower MDI andPDI at 12 m and 24 m 1–3 m; 4–6 m; 7–9 m (within 6 m Correlations; hierarchical linear More severe objective stress after ice storm, in many cases BSID-Mental scale by observer exposure associated with lower Age: 30.6 (20–42) yr during pregnancy) MacArthur Communicative Controlled for: birth weight, gen- MDI and lower productive and Objective stress measure of dis- Development Inventory (French der, month of gestation, age at receptive language abilities on aster; treat, loss, scope and change MacArthur Inventory; effects on Subjective stress measure: Impact (SES, pregnancy and birth com- MDI only significant for stress of Event Scale Revised plications, postpartum depression during first six months of preg- nancySubjective stress measure notrelated to MDI or languageabilities NZ7447 (from cohort) Logistic regressioncontrolled for: High levels of anxiety at 32 wk Anxiety items of the Crown-Crisp 3595 girls, 3853 boys timing of prenatal anxiety, birth associated with more inattention/ Age: 28 (14–46) yr Strengths and Difficulties Ques- weight for gestational age, mode hyperactivity and emotional pro- tionnaire (SDQ), by mother of delivery, parity, smoking, alco- blems in boys and with more hol, SES, maternal age, postnatal emotional and conduct problems anxiety and depression (EDPS) in girlsHigh levels of anxiety at 18 wkassociated with more emotionalproblems in girls NZ527–1297 (6 m) and NZ389– 1–16 wk; 17–28 wk; 29–40 wk Correlations; latent variable path Psychological distress modestly 900 (5 yr) (from cohort) Self-construct pregnancy ques- 50% male (6 m) 54% male (5 yr) related to negative temperament at tionnaire on psychological distress ITQ and Preschool Temperament Controlled for: somatic illness, 6 m.; strongest for psychological (anxiety/depression and mood Questionnaire (adapted), by nausea, maternal age distress at 1–16 wk Higher psychological distress at 1–16 wk related to higher negativeemotionality at 5 yr; strongest for More risks during pregnancy Infant temperament questionnaire associated with lower school (self-construct), by mother (6 m) grades and more negative behavior School grades and marks for in school at 6 yr behavior in school, by two tea-chers (6 yr) Z6204–6493 (from cohort) Logistic regression High levels of anxiety at 32 wk Anxiety items of the Crown-Crisp 3000 girls, 3204 boys Controlled for: timing of prenatal associated with more behavioural/ Age: 28 (14–46) yr anxiety, birth weight for gesta- emotional problems in both boys tional age, mode of delivery, parity, smoking, alcohol, SES, High levels of anxiety at 18 wk maternal age, postnatal anxiety associated with more behavioural/ and depression (EDPS) emotional problems in girls (effectof 18 wk stronger than effect of 10; 12; 20; 28; 32; 36 wk Correlations, linear and logistic High stress and heavy smoking Swedish 10-item version of Per- 146 girls, 142 boys independently associated with ceived Stress Scale 18 symptoms (DSM-IV criteria for Controlled for: smoking, timing of more ADHD symptoms; fulfill- ADHD), by mother and teacher stress and smoking, maternal edu- ment of diagnostic criteria for Impact item of the SDQ, by cation and civil status, presence ADHD related to prenatal stress and salary of father figure Week 10 accounted for the largestportion of the variance (continued on next page) Table 3 (continued) Anxiety/stress measure in preg- Outcome assessment: Statistical analyses: Impact of antenatal anxiety/stress: Size at outcome, characteristics of Child's age at outcome; gender; Method; confounders controlled Negative child outcome (normal Timing; questionnaires; physio- measures; observer letter); positive and zero effect NZ71 (72 children) 12–22 wk; 23–31 wk; 32–40 wk Correlations, hierarchical linear Higher anxiety at 12–22 wk Nulliparous: 100% STAI-state anxiety 34 girls, 38 boys associated with more ADHD Composite score for ADHD Controlled for: timing of prenatal symptoms and externalizing pro- No medical or psychiatric pathol- symptoms, externalizing and anxiety, postnatal trait anxiety, blems and with higher self report internalizing problems based on: educational level, smoking, birth CBCL, by mother and teacher; weight for gestational age, gender Anxiety at 32–40 wk not a signifi- Conners' Abbreviated Teacher cant independent predictor of Rating Scale, by mother and (Prechtl's Obstetric Optimality childhood disorders teacher; Groninger Behaviour Observation Scale, by external observerSTAIC, by child 12–22 wk; 23–31 wk, 32–40 wk Correlations; MANCOVA's High state anxiety at 12–22 wk is Nulliparous: 100% 28 girls, 29 boys Controlled for: timing of prenatal related to impulsive cognitive Performance of child on compu- anxiety, postnatal trait anxiety style (reacting faster but making No medical or psychiatric pathol- terized Encoding Task and Stop (Educational level, birth weight more errors) in the Encoding task for gestational age, smoking, Pre- and to lower scores on the intelli- Vocabulary and Block Design of chtl's Obstetric Optimality Score) gence subtests, but not to Stop Wisc-R intelligence test Task performance.
No effect of trait anxiety and no effect of state anxiety at 23–31 and32–40 wk on encoding, Stop Task,or intelligence subtests wk, week(s); m, month(s); ACTH, adrenocorticotrophic hormone; ADHD, Attention-Deficit Hyperactivity Disorder; SES, Socio-Economic Status; temp., temperament. Abbreviation of Scales: BDI, Beck Depression Inventory; BSID, Bayley Scales of Infant Development; CBCL, Child Behavior Checklist; EPDS, Edinburgh Postnatal Depression Scale; GHQ, General Health Questionnaire; IBR, Infant BehavioralRecords; ICQ, Infant Characteristics Questionnaire; ITQ, Infant Temperament Questionnaire; MDI, Mental Developmental Index; NBAS, Neonatal Behavior Assessment Scale; PDI, PsychomotorDevelopmental Index; STAI, State Trait Anxiety Inventory; STAIC, State Trait Anxiety Inventory for Children; SDQ, Strengths and Difficulties Questionnaire; aAll studies in this table are prospective follow-up studies of the period 1985–2004. Under the heading ‘Sample‘ characteristics of the mothers are given out of which eligibility criteria can be inferred. Under the headings ‘Anxiety/stress measures in pregnancy' and ‘Outcome assessment' those variables are given that were reported in the articles (between brackets: variables not used in the statistical analyses). Under the heading ‘Statistical analyses' the variables arelisted that were controlled for in the described statistical analysis method (between brackets: confounders not used in the statistical analyses). Under the heading ‘Impact of antenatal anxiety/stress' only thosenegative, positive and zero effects are presented that were reported in the article.
B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 disorders measured with the Child Behavior Checklist up child behaviour persisted even after controlling for potential to 14–15 years of age.
confounders in the pre and/or post-natal period, lendssupport to the idea that fetal programming by antenatal 3.2. Controlling for the effect of confounders anxiety/stress is occurring in humans, as in the animalmodels. It is likely that the effects of the changed prenatal It is important to ask whether the good evidence for a link environment interact with genetic factors in defining the between antenatal maternal anxiety/stress and regulation phenotype at birth . Those studies, which have problems in the child, also implies fetal programming examined the same sample at two or more times, show induced directly by maternal anxiety/stress. The link may be the same effects persisting with the same magnitude over 3 mediated by other prenatal or post-natal environmental (nos. 11, 14) and 9 years (nos. 6, 16). Although more factors, such as smoking during pregnancy or post-natal research is needed to study the potential modulating effect maternal anxiety, or may be explained by rater bias. There of other post-natal factors than post-natal mood (e.g.
may also be a genetic vulnerability passed directly from attachment and parenting style) , all these long- mother to child. The underlying mechanism is likely to be a term results again support a prenatal programming prenatal programming one if the link can be shown to be specifically with antenatal and not post-natal anxiety/stress,if it cannot be explained by rater bias, and if the link persists 3.3. Timing of gestational stress after controlling for the effect of other prenatal environ-mental factors. Several studies have attempted to control forthese confounders.
Studies are inconsistent with regard to the gestational age For measuring anxiety or stress during pregnancy all at which the effects of antenatal maternal anxiety/stress are studies used mother's self rating of symptoms or events, most pronounced. Rodriguez and Bohlin (no. 15; rather than a clinical diagnosis. Studies 1, 3, 7, and 8 also concluded that stress at week 10 accounted for the largest included stress hormone measures (Some studies proportion of the variance in ADHD-symptoms at age 7, and have analyzed specific pregnancy anxieties (no. 8) or the Martin et al. (no. 12) found the strongest effect on negative number of life events and/or appraisal of recently experi- emotionality in 5-years-old for psychological distress enced life events (nos. 1, 2, 8) or disaster (no. 10) during during the first three months of pregnancy. Laplante et al.
pregnancy, which indicates that the anxiety and stress are (no. 10) found that high levels of objective stress exposure likely to be more specific to the antenatal period. Most other (measured within 6 m after an ice storm) affected intellec- studies used standardized scales (nos. 3, 5–11, and 14–17) tual capacities at age 2 only when the stress occurred in the or assembled a scale (nos. 4, 12, 13) to measure perceived first six months of pregnancy. Van den Bergh (nos. 16, 17) anxiety and stress confined to the prenatal period. As the found that effects on childhood disorders at age 8–9 and perception of anxiety in pre- and post-natal periods are cognitive functioning at age 14–15 were confined to significantly correlated associations found maternal anxiety at 12–22 weeks of pregnancy. Huizink between antenatal anxiety/stress and child's outcome can and colleagues (no. 8) found more pronounced effects for be spurious. However, studies nos. 5, 6, 8, 9, 11, 14, 16, and maternal anxiety/stress at 15–17 weeks and pregnancy- 17 used a multivariate analysis including measures of specific anxieties at 27–28 weeks, while early morning perceived post-natal anxiety and/or depression and/or stress cortisol levels at 37–38 weeks had a small effect. O'Connor as confounding variables, and still found strong links et al. (nos. 11, 14) found that anxiety at week 32 was a between antenatal maternal anxiety and regulation problems stronger predictor of behavioural/emotional problems at age in the child.
4 and 7 than anxiety at 18 weeks.
Studies nos. 2, 11, and 14 have used large numbers, which The fact that several gestational ages have been reported gives a good opportunity to not only control for post-natal but to be vulnerable to the long-term effects of antenatal also for antenatal confounding variables, e.g. for educational anxiety/stress may indicate that different mechanisms are level and income, smoking, parity, birth weight, gestational operating at different stages. However, observed differences age, and gender of the child. The other studies, using smaller in effects of timing may also be due to differences between numbers, controlled in their statistical analyses at least for the studies, including the scales used for dependent and confounders shown in their own sample to be influential (nos.
independent variables (see the exact timing of the 1, 5–10, 12, 15–17). Moreover, potential confounders were anxiety measurements, the time period to which they refer, also controlled by using strict eligibility criteria, e.g. for as well as to the intensity of anxiety and the actual parity, age, medical, obstetrical and psychiatric risks (see persistence of anxiety throughout pregnancy In nos. 1, 3, 5–9, 16, 17). Only study nos. 3, 4, 7, and 13, and one addition, genetic differences and differences in psychologi- report of study no. 6 showed insufficient control for cal, medical–obstetrical, and environmental factors con- confounders in their design or statistical analyses.
trolled for and not controlled for might be relevant We can conclude that the fact that in most studies the link This is clearly an area that needs more attention between antenatal maternal emotions and later infant or in future research.
B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 3.4. Magnitude of the effect epinephrine levels and not to the higher rates of low birthweight and prematurity Zuckerman et al. observed It is important to assess the amount of variance in that babies of women with depressive symptoms (NZ1123) outcome that may be related to antenatal maternal emotions.
cried excessively at 8–72 h after birth and were difficult to Several of the studies show associations large enough to be console; no effects were found on neurological state.
of clinical significance (nos. 10, 11, 14–16; ). For Dawson and colleagues have found that during mother– example, in study no. 10, maternal stress exposure to an ice infant interaction, children of depressed mothers showed storm at 0–12 weeks and 13–24 weeks of pregnancy increased autonomic arousal (higher than normal heart rates explained 27.5 and 41.1% of the variance in the Bayley MDI and cortisol levels), and reduced activity in brain regions scores at age 2, respectively. In studies nos. 11 and 14, being that mediate positive approach behaviour The authors in the top 15% for antenatal anxiety at 32 weeks of indicate that there is suggestive evidence from their follow- gestation, approximately doubled the risk for having a son up study (NZ159 at 13–15 m; partial follow-up to 42 m with ADHD symptoms at age 4 and 7, even after allowing ) that the post-natal experience with the mother had for a wide range of covariates including post-natal anxiety more effect on infant frontal EEG than prenatal factors.
up to 33 m. Study no. 6 indicates that maternal anxiety at O' Connor et al. examined antenatal depression as 12–22 weeks explained 15 and 22% of the variance in well as anxiety, using the self-rating Edinburgh Post-natal externalizing problems and ADHD symptoms at age 8–9, Depression Scale antenatally as well as post-natally.
respectively. Other studies show more modest effects. In Antenatal depression had a somewhat weaker effect on study no. 8, for instance, 3–8% of the variance in child outcome than antenatal anxiety. When both were used behavioural regulation and mental and motor development together in a multivariate analysis, the effects of antenatal at 3 and 8 m was explained, mainly by specific anxiety/ anxiety were apparent but not those of antenatal depression.
stress at 15–17 and 27–28 weeks of gestation , and In contrast, the effects of post-natal depression were found no effect of state or trait anxiety during these periods was to be separate but additive to those of antenatal anxiety .
Ma¨ki et al. in a prospective epidemiological study Differences in the amount of explained variance may be (NZ12,059), found that in the male offspring of antenatally related to the timing of anxiety/stress (see above) or to a depressed mothers there was a significant but only slight difference in the degree of anxiety/stress experienced by the increase in criminality.
pregnant women across the different studies. For instance, instudy no. 8, mean state anxiety was 32.9 (SDZ7.8) at 15–17 3.6. Effects of antenatal anxiety/stress on handedness weeks and 31.1 (SDZ8.4) at 37–38 weeks of gestation These values equal decile 4, thus below the mean, of a Studies that looked at handedness have shown Dutch female norm population In study no. 6, mean that antenatal life events or anxiety are associated with a state anxiety in comparable gestation periods was 38.7 greater incidence of mixed handedness in the child. This (SDZ7.7) and 36.1 (SDZ8.8), equaling decile 6 and decile was defined as the child using either hand for a range of task 5 of the same norm population, respectively.
such as drawing or throwing a ball. While in itself not abehavioural problem, mixed handedness has been shown to 3.5. Effects of antenatal maternal depression, a co-morbid be associated with a range of neurodevelopmental problems symptom of anxiety such as dyslexia, autism, and ADHD. This mild adverseeffect would again fit with the animal research in which a Much more research has been done on the effects of wide range of disturbances have been found in the offspring, antenatal anxiety than depression, although it is well including a disturbance of laterality .
established that there is a strong co-morbidity between thetwo Field's group has performed a range of studies on 3.7. Weaknesses of the studies the outcome for the newborn baby with mothers who weredepressed during pregnancy . They showed that One weakness of many or most of the studies concerns maternal depression during pregnancy was significantly the outcome measures. Researchers did not use specific associated with less than optimal scores on many subscales marker tasks for testing specific cognitive functions (e.g.
of the Brazelton Neonatal Assessment Scale (e.g. habitu- attention, inhibition, working memory, processing speed).
ation, orientation, autonomic stability), with lower vagal Nor did they use neuro-imaging techniques, such as electro- tone, and with a greater relative right frontal EEG encephalogram, event related potentials, and (functional) activation. Elevated cortisol and norepinephrine, and magnetic resonance imaging, or neuroendocrine measures.
lower dopamine and serotonin levels in the newborn were In some studies of infants, the Bayley Scales of Infant also found A structural equation model indicated Development were used. Although these instruments are that the less than optimal neonatal behavioural profile, in useful as descriptive instruments and allow identification of which 8–21% of the variance was explained, was related to certain sensorimotor deficits, they are rather global antenatal maternal depression and to cortisol and measures. In addition, scores on these tests have proved to B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 be largely unrelated to scores on intelligence tests in later hypothesis is that maternal stress hormones, and in childhood (p. 33). Marker tasks provide more specific particular, glucocorticoids, are transmitted across the outcome measures. They are used in developmental placenta . A second possible mechanism is via an effect cognitive neurosciences and behavioural teratology on uterine artery blood flow .
research to indirectly identify which underlyingstructure–function relations are altered. Neuro-imaging 4.1. Transfer of hormones across the placenta techniques could elucidate some of the altered structure–function relations and underlying mechanism in a more In utero exposure to abnormally high levels of maternal direct manner. Using neuroendocrine measures, especially glucocorticoids is one plausible mechanism by which under stress-inducing situations, has the potential to maternal stress may affect the fetus. However, the placenta elucidate if and how the stress-regulating system is involved is an effective barrier between the maternal and fetal in the regulation problems of the offspring.
hormonal environments in humans, being rich in protective A second weakness is that it is not always clear whether enzymes such as monoamine oxidase A, peptidases, and or not women were excluded who took medication such as 11b-hydroxysteroid dehydrogenase type 2, which converts antidepressants during pregnancy cortisol to inactive products such as cortisone The Third, although maternal coping mechanisms and impact of maternal stress on this enzyme is not known; there characteristics such as optimism can interact is some evidence that it is reduced in intrauterine growth with anxiety/stress or have an independent effect, only a restricted pregnancies .
few of the studies have included these measures. For The links between maternal and fetal hormonal levels instance, an unpublished result of study no. 6 revealed that have been examined by studying the correlation between use of emotion-focused coping (i.e. subscales expression of maternal and fetal plasma levels for a range of hormones emotions and social support of the Utrecht Coping list (). Comparing levels of cortisol in paired maternal had a positive effect on both psychomotor develop- and fetal plasma samples, showed that fetal concentrations ment (BZ6.13, p!0.0001) and mental development were linearly related to maternal concentrations .
(BZ2.76, pZ0.044) and uniquely explained 17.8 and As maternal concentrations are substantially higher than 6.5% of the variance, respectively, after control for the fetal (over 10-fold), this is compatible with substantial confounders listed under study no. 6 (State (80–90%) metabolism of maternal cortisol during passage anxiety was unrelated to this coping style (r [70]Z0.030; across the placenta, and is in accord with in vivo and ex vivo studies . However, it does suggest that if the A fourth concern is that most of the studies have not mother is stressed in a way that increases her own cortisol looked for gender effects. Those studies that did (nos. 11, level, this will be reflected in the hormonal milieu of the 12, 14–17) found some suggestion that boys were more fetus. This mechanism cannot underlie the immediate links susceptible to the influence of maternal anxiety and stress.
that have been observed between changes in maternal mood, To conclude, the evidence for a link between antenatal e.g. in anxiety while doing a cognitive test, and fetal maternal anxiety/stress and regulation problems at the behaviour as plasma cortisol takes about 10 min cognitive, behavioural, and emotional levels in the child is to respond to a stressor.
persuasive because this link has been replicated in 14 With both b-endorphin and noradrenaline independent studies, with children ranging from birth up to there was no significant correlation between maternal and 15-years-old. Moreover, this link generally persisted after fetal plasma levels. Neither b-endorphin nor noradrenaline controlling for post-natal maternal mood and/or other is lipophilic, and neither would be expected to cross cell potentially important pre- and post-natal confounders. The membranes as readily as the steroid, cortisol. Corticotrophin study of the timing, intensity and chronicity of anxiety/ releasing hormone (CRH) is correlated in the maternal and stress, of maternal coping mechanisms and gender of the fetal compartments of the placenta but to a lesser child on a variety of neurodevelopmental aspects (includinghandedness) needs more attention. The use of marker tasks of specific cognitive functions, neuro-imaging techniques, Correlations between maternal and fetal hormone levels and neuroendocrine measures could elucidate some of the altered structure–function relationships and some under- lying mechanisms.
4. Two physiological mechanisms by which the maternal affective state may affect the fetus in humans Giannakoulo-poulos 1999 Two mechanisms of transmission of anxiety/stress from mother to fetus in humans have been suggested. One B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 degree than cortisol. Being a peptide, it is unlikely to cross of 40 and more) had significantly worse uterine flow from mother to fetus, and it is therefore more probable that velocity waveform patterns than those in the lower anxiety CRH is secreted into both compartments from the placenta, groups. This finding on abnormal uterine blood flow under some partial form of joint control. Testosterone, a parameters in highly anxious women was recently con- steroid like cortisol, is highly correlated in the two firmed in a larger cohort where an association between compartments, and it is plausible that there is some direct maternal anxiety and uterine blood flow was present at 30 transfer from mother to fetus. Recently, it has also been but not at 20 weeks of gestation (Jackson, Fisk and Glover; shown that, unlike the norm in the adult, there is a positive correlation between fetal plasma cortisol and testosterone A study by Sjo¨stro¨m and colleagues aimed at levels Cortisol and testosterone in the fetus are clearly determining whether fetal circulation was affected by not under identical control; there are likely to be several maternal anxiety, found that, in the third trimester, fetuses different determinants of fetal testosterone levels. Fetal of women with high trait anxiety scores had higher indices testosterone levels are higher in males than females but of blood flow in the umbilical artery, and lower values in the there is no difference in cortisol in the two sexes. Whereas fetal middle cerebral artery, suggesting a change in blood there is an increase in testosterone with gestational age in distribution in favour of brain circulation in the fetus. These females there is no such increase in cortisol over this age results indicate that raised maternal anxiety, even within a range. However, the mechanism of inter-related control of normal population, had an influence on fetal cerebral the HPA axis and testosterone production is different in the fetus compared with the adult. Thus it may be that in the We do not know whether these associations between fetus some of the factors that cause raised fetal cortisol level anxiety and Doppler patterns are acute or chronic. Further may also cause an increase in testosterone level. This is work is needed to determine whether overall anxiety during compatible with a mechanism by which maternal stress may pregnancy or even prior to or at conception, might affect influence fetal development in ways associated with a more later uterine artery blood flow patterns, or instead, whether masculine profile, including an increase in mixed handed- the association is only with the current emotional state. We ness, ADHD and learning disabilities.
also need to determine whether the magnitude of the link There have been very few studies examining the between maternal anxiety and uterine blood flow is function of the maternal HPA-axis during pregnancy in sufficient to be of clinical significance.
relation to her emotional state. Obel observed that In pregnant sheep infusion of noradrenaline decreased evening, but not morning salivary cortisol was raised in uterine blood flow, indicating the possibility that high women with high perceived life stress at 30 weeks, but not anxiety can cause acute changes in uterine artery blood flow at 16 weeks of gestation. Rieger et al. found no In addition, in sheep, reproductive tissues including significant influence of perceived maternal stress on the uterus are more sensitive to the vasoconstrictive effects awakening cortisol response, neither in the first, nor in of noradrenaline than other body tissues. However, other the third trimester. Cortisol rises markedly at the end of animal studies have also indicated the possibility that gestation, and the mother's HPA-axis becomes desensi- maternal stress or anxiety, early in gestation, might affect tized to stressors as her pregnancy develops the later uterine blood flow. In a rat model study cold stress presumably due to the large amounts of CRH which are early in pregnancy decreased trophoblastic invasion. This released from the placenta. We do not know exactly when, was followed by increased blood pressure, raised blood and by how much this desensitization occurs.
catecholamine levels, and proteinuria in later pregnancyThe authors suggest they have produced a model for 4.2. Impaired uterine blood flow preeclampsia, mediated by increased catecholamines caus-ing decreased trophoblastic invasion.
The hypothesis that anxiety in pregnant women is To conclude, there is good evidence for a strong associated with abnormal blood flow in the uterine arteries correlation between maternal and fetal cortisol levels.
was tested using colour Doppler ultrasound to measure the Thus if the mother is stressed in such a way as to raise blood flow pattern and an according to standard procedures fetal cortisol, the fetal environment may be changed in a calculated Resistance Index (RI) A high RI indicates way that could have long term effects. However, this a greater resistance to blood flow, and is known to be mechanism cannot underlie the immediate links between associated with adverse obstetric outcome, particularly maternal mood and fetal behaviour. Noradrenaline, which intrauterine growth restriction and preeclampsia. The can respond in seconds, does not appear to cross from resulting lack of oxygen may also cause a direct stress to mother to fetus, but may have an indirect effect via the fetus. Significant associations between the RI in the changes in the maternal muscular or vascular tone. This in uterine artery and both state and trait anxiety were found in a turn may cause stress to the fetus and raise cortisol levels.
sample of hundred women with singleton pregnancies, However, much remains to be understood. We need to measured between 28 and 32 weeks of gestation. Women in know more about the biochemical correlates of normal the highest anxiety groups (Spielberger's state anxiety score variations and of high anxiety, stress and the response to B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 life events in the pregnant woman at different periods of period. In lower parts of the brain (e.g. in the nuclei of the gestation. We also need to know what happens when brainstem and reticular formation) the first neurons are cortisol levels are raised in the fetus. How does this affect produced in the 4th week after conception (6th week the development of the nervous system and of other postmenstrual age). The basal ganglia become visible systems, infant growth, age at delivery, and later during the 6th postconceptional week, when the ganglionic behaviour? We need to be aware that these may all be eminence develops In the cerebral cortex, almost all affected by different mechanisms.
neurons are generated at 6–18 weeks after conception. Aftertheir birth, neurons start migrating; the last born neuronsarrive at their final place in the cortex at about 23–24 weeks 5. Stress hormones and the developing fetal nervous of gestation During migration, differen- system: how are they related to behavioural/emotional tiation of the neuron starts, resulting in the final phenotype regulation problems in infants and children? of the neuron. The prefrontal cortex differentiates ratherlate: only at 26–34 weeks of gestation is its basic 6-layered There is evidence that complex functions such as cytoarchitectonic pattern established . In contrast, in behavioural and emotional regulation, are mediated through the limbic system (e.g., the hippocampus, amygdala) and the prefrontal cortex (PFC). The PFC has many subdivisions limbic regions of the cortex (e.g. anterior cingulate cortex) and collectively these areas have extensive and reciprocal the major nuclei are already formed during the third and connections with all sensory systems, cortical and sub- fourth month; at 16 weeks the hippocampal area begins to cortical motor system structures, subcortical arousal and differentiate into the hippocampus proper and the dentate attention functions, and with limbic and midbrain structures gyrus Although differentiated early, the dentate gyrus involved in affect, memory, and reward Behavioural displays continued post-natal proliferation of granule cells; functions are not localized in the PFC, rather the PFC about 85% is formed at birth Proliferation of granule (through the action of its subdivisions) seems to be essential cells continues also in the cerebellum for several months for the control of organized, integrated functioning after birth .
For example, the medial part, including the anterior Synaptic maturation includes the growth of axons and cingulate cortex (ACC), controls a range of functions, dendrites, axonal projections, synaptogenesis and myelina- such as motivation, drive to perform, response selection, tion. Correct timing and exclusion of inappropriate connec- working memory, and novelty detection It is tions (‘synaptic pruning') are essential for the maturation of therefore of interest to determine how prenatal stress may synaptic connections. Also apoptosis, or programmed cell affect the development of the PFC and ACC and of areas death, is necessary for proper development of the central related to these regions.
nervous system, as about 50% of all generated neurons die.
Proper timing and guidance of neurogenesis, neuronal In the neocortex, the first synapses are formed around 8 differentiation and migration, apoptosis, synaptogenesis and weeks of gestation, although at a very low density .
myelination, are critical for the appropriate organization and Different genes and their products (e.g. various transcription functioning of the neocortex. These processes are controlled factors and growth factors) are involved in early axon by mechanisms intrinsic to the cell and processes extrinsic guidance Until 23–24 weeks of gestation to the cell, i.e. by genes and their products, by cell–cell intrinsic (experience-independent) processes guide axonal interactions, by interactions of cells with early neurotrans- growth and synaptogenesis; at 23–24 weeks thalomo- mitters and neuromodulators acting as growth factors cortical circuits become functional and from then onwards It is important to note that, although before 23 weeks of (and throughout life) experience-dependent processes are gestation these developmental processes are not driven by important, first in expanding and afterwards in fine-tuning activity that is modulated by sensory input, they never- the neuronal circuits. Experience also induces modifications theless can be altered This happens when environ- in glial cells and cerebrovasculature . Clusters of mental factors (e.g. viruses, tobacco, cocaine, cortisol) genes are exclusively expressed in correlation with high modulate the influence of intracellular and extracellular levels of developmental plasticity (e.g. in the visual cortex developmental signals. In general, the earlier the disturb- this again illustrates the importance of the ance occurs, the greater its potential influence on sub- interaction between genes and environment (in casu sequently occurring events and maturation, and finally, on experience) for developmental cortical plasticity the mature structure–function relationship .
In animal models, glucocorticoids are known to be Although region-by-region differences in timing exist, involved in fetal programming of the HPA-axis and neurogenesis, neuronal differentiation and migration occur neurotransmitter systems (for a review see , before the 7th month of gestation for most parts of the and Owen et al. Antenatal maternal treatment with nervous system. Knowledge of these differences is import- synthetic glucocorticoids, such as betamethasone and ant for delineating which cortical layers or areas (and hence dexamethasone, has been shown to have a range of long- processes) might have been altered by a disturbing term effects on child behaviour and cognitive development environmental agent, acting during a particular gestational However, we currently know very little of B.R.H. Van den Bergh et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 237–258 the influence of stress hormones on the developing human consequences. Prenatal programming of the HPA-axis and fetal nervous system. It is clear that, although cortisol is of structure–function relationships controlled by the pre- essential for normal brain development, exposure to frontal cortex may contribute to regulation problems at the excessive amounts has long-lasting effects on neuroendo- cognitive, behavioural, and emotional level of children of crine functioning and on behaviour. Glucocorticoids mothers with high anxiety/stress during pregnancy. The (cortisol in humans) are known to have profound effects disturbance of the particular developmental processes upon the developing brain and spinal cord; they can taking place in specific brain layers and areas at the time modulate cell proliferation and differentiation and synaptic of antenatal maternal stress hormone release, in interaction development in various brain regions If for with the genetic susceptibility of the offspring and mediated instance, in the third or fourth month of gestation, a by later pre and post-natal environmental factors, will teratogen such as cortisol modulates the influence of determine the way in which cognitive, motor, arousal, and developmental signals and disrupts neuronal migration, emotional structure–function relationships are altered this may result in abnormal cell density and cell position in The ways in which the PFC integrates these altered the different layers of the anterior cingulate cortex. This processes presumably underlie the kind of behavioural/ pattern, which has been reported in postmortem cases of emotional regulation problems these children will even- schizophrenia and bipolar disorders results in alterations of different neurotransmitter systems in thecorticolimbic region . During the onset of differen-tiation (e.g. at about 16 weeks in the hippocampus and 6. General conclusions between 26–34 weeks in the prefrontal cortex) disturbancesby teratogens can alter the timetable of the expression of This review shows that there is good evidence for a several neurotransmitters, neuropeptides (e.g. CRH), and direct link between antenatal anxiety/stress and fetal their receptors. This in turn can alter receptor sensitivity as behaviour observed by ultrasound from 27 to 28 weeks well as dendritic outgrowth and formation of synapses, and postmenstrual age onwards. There is also accumulating change the balance between excitatory and inhibitory brain evidence that there are links between maternal mood during pregnancy and the long-term behaviour of her child.
Two recent studies are of interest in the context of The fact that maternal anxiety/stress during pregnancy is perinatal programming. Roberts et al. have recently linked with later behaviour, even after controlling for examined the relationship between the striatal dopamine effects of post-natal maternal mood and other relevant system integrity and behaviour in 5-to 7-year-old rhesus prenatal and post-natal confounders, does suggest that, as monkeys born from mothers that were exposed to stress in animal models, a programming effect on the fetal brain during late pregnancy . They have previously shown is taking place. It is clear that many different underlying altered HPA-axis function and behaviour in such offspring.
mechanisms and systems are involved in perinatal In their new study, subjects from prenatal stress conditions programming. Based on the available evidence it seems showed an increase in the ratio of striatal dopamine D2 plausible that fetal programming of the HPA-axis, limbic receptors and DA synthesis compared to controls, in a way system, and prefrontal cortex may contribute to the which they conclude supports a hypothesis linking striatal regulation problems found in children of mothers who function to behavioural inhibitory control. Lou et al. found a were highly anxious/stressed during pregnancy. Many link between high dopamine D2/3 receptor availability questions remain on exactly how fetal programming (examined with positron emission tomography) and inhi- works in humans, and in which specific ways the timing, bition failure (expressed in increased reaction time and kind, intensity, and duration of environmental disturbances reaction time variability during a computerized attention are related to altered neurobehavioural development. The task) in 27 prematurely born adolescents with ADHD mechanisms underlying either direct links or fetal pro- Interestingly, high dopamine receptor availability was gramming in humans are only just starting to be predicted by low neonatal cerebral blood flow. This could contribute to a persistent deficiency in dopaminergic However, there is enough evidence now to warrant active neurotransmission. Results of these studies are congruent research into prevention, intervention, and support pro- with results of Durston et al. in which event-related grams to reduce stress or anxiety during pregnancy and their functional magnetic resonance imaging indicated that effects on child outcome. These programs could include children with ADHD did not activate fronto-striatal regions stress reduction instructions (e.g. and cognitive- during go/no-go tasks in the same manner as control behavioural treatments to reduce anxiety from early children, but rather relied on a more diffuse network of gestation on, or even before conception (e.g. Research on underlying mechanisms, on the effect of the To conclude, disturbance of the delicate balance of timing, intensity and duration of anxiety/stress, and the factors guiding the precisely timed neocortical neurogenesis effect of gender, can be carried out in parallel, and actually and synaptogenesis during gestation can have long-term would be helped by successful intervention strategies.
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