Vivette Glover

Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review.

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 other relevant confounders in the pre- and post-natal periods. Although some inconsistencies remain, the results in general support a fetal programming hypothesis. Several gestational ages have been reported to be vulnerable to the long-term effects of antenatal anxiety/stress and different mechanisms are likely to operate at different stages. Possible underlying mechanisms are just starting to be explored. Cortisol appears 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-term effects of antenatal maternal anxiety/stress on the child is substantial. Programs to reduce maternal stress in pregnancy are therefore warranted.

Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis

BACKGROUND Previous animal investigations link antenatal stress with a range of persistent behavioural abnormalities in the offspring. The current study examined if the effect was also found in humans through middle childhood. METHODS The current study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective, community-based study that has followed a cohort of women from pregnancy. Self-report measures of maternal anxiety and depression were assessed at repeated intervals in pregnancy and the postnatal period. Childrens behavioural/emotional problems were assessed by parent report at age 47 and 81 months. Information on obstetric and psychosocial factors was obtained at several points in pregnancy and the postnatal period. RESULTS Children whose mothers experienced high levels of anxiety in late pregnancy exhibited higher rates of behavioural/emotional problems at 81 months of age after controlling for obstetric risks, psychosocial disadvantage, and postnatal anxiety and depression (for girls, OR = 1.91, 95%CI = 1.26-2.89; for boys, OR = 2.16, 95%CI = 1.41-3.30). Furthermore, the effect at 81 months was comparable to what was previously obtained at 47 months, suggesting the kind of persistent effect proposed in the animal literature. CONCLUSIONS There is evidence that antenatal stress/anxiety has a programming effect on the fetus which lasts at least until middle childhood.

Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study

Abstract Objective: To investigate whether maternal anxiety in the third trimester is associated with an increased uterine artery resistance index. Design: Cohort based study. Subjects: 100 pregnant women, with a mean gestation of 32 weeks. Outcome measures: Self rating Spielberger questionnaire for state anxiety and trait anxiety, and uterine blood flow waveform patterns as assessed by colour Doppler ultrasound. Results: A significant association was found between uterine artery resistance index and scores for both Spielberger state anxiety and trait anxiety (rs=0.31, P<0.002 and 0.28P<0.005 respectively). Women with state anxiety scores >40 (n=15) had a higher mean uterine resistance index than those with scores —40 (mean difference with mean resistance index 24%, 95% confidence interval 12% to 38%; P<0.0001). Similarly, women with trait anxiety scores >40 (n=32) had a higher mean resistance index than those with scores —40, although to a lesser extent. The presence of notches in the waveform pattern produced by uterine artery blood flow was found in 4/15 (27%) women with high state anxiety scores compared with 4/85 (5%) with low anxiety scores (P<0.02). Conclusions: This study shows an association between maternal anxiety in pregnancy and increased uterine artery resistance index. It suggests a mechanism by which the psychological state of the mother may affect fetal development, and may explain epidemiological associations between maternal anxiety and low birth weight. The influence of maternal anxiety may be one mechanism by which the intrauterine environment contributes to later disease in offspring.

Antenatal Anxiety Predicts Child Behavioral/Emotional Problems Independently of Postnatal Depression

OBJECTIVE To examine the hypothesis that the effects of postnatal depression on childrens behavioral/emotional problems are explained by antenatal maternal mood. METHOD The current study investigated this hypothesis in the Avon Longitudinal Study of Parents and Children, a prospective, community-based study that has followed a cohort of women since pregnancy (n = 7,144) who delivered their baby between April 1, 1991, and December 31, 1992. Self-report measures of maternal anxiety and depression were assessed at repeated intervals in pregnancy and the postnatal period. Childrens behavioral/emotional problems were assessed by parent report at age 4 years. RESULTS After controlling for smoking, alcohol use, birth weight for gestational age, maternal age, child sex, and socioeconomic status, postnatal depression at 8 weeks (OR = 2.27 [1.55-3.31]) and 8 months (OR = 1.68 [1.12-2.54]) was associated with childrens behavioral/emotional problems. Subsequent analyses that included antenatal maternal mood indicated that antenatal anxiety in late pregnancy and not antenatal depression was also independently associated with behavioral/emotional problems at age 4 (OR = 1.72 [1.14-2.59]); 8 week postnatal depression remained a significant predictor after antenatal maternal mood was statistically controlled for (OR = 1.56 [1.04-2.32]). CONCLUSIONS Antenatal anxiety and postnatal depression represent separate risks for behavioral/emotional problems in children and act in an additive manner.

Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children

BACKGROUND Animal studies suggest that prenatal stress is associated with long-term disturbance in hypothalamic-pituitary-adrenal (HPA) axis function, but evidence in humans is lacking. This study examined the long-term association between prenatal anxiety and measures of diurnal cortisol at age 10 years. METHODS Measures of cortisol were collected at awakening, 30 min after awakening, and at 4 pm and 9 pm on 3 consecutive days in a sample of 10-year-olds (n = 74) from the Avon Longitudinal Study of Parents and Children, a prospective longitudinal cohort study of mothers and children on whom measures of anxiety and depression were collected in pregnancy and the postpartum period. Analyses examined the links between symptoms of prenatal anxiety and multiple indicators of cortisol, an index of HPA axis functioning. RESULTS Prenatal anxiety was significantly associated with individual differences in awakening and afternoon cortisol after accounting for obstetric and sociodemographic risk (partial correlations were .32 and .25, p < .05). The effect for awakening cortisol remained significant after controlling for multiple postnatal assessments of maternal anxiety and depression. CONCLUSIONS This study provides the first human evidence that prenatal anxiety might have lasting effects on HPA axis functioning in the child and that prenatal anxiety might constitute a mechanism for an increased vulnerability to psychopathology in children and adolescents.

Prenatal stress and the programming of the HPA axis

There are several independent prospective studies showing that a wide variety of forms of prenatal stress can have long-term effects on the behavioural and cognitive outcome for the child. Animal studies have shown that prenatal stress, as well as affecting behaviour, can also reprogram the function of the HPA axis in the offspring. However, the effects on the HPA axis are very variable depending on the nature of the stress, its timing in gestation, the genetic strain of the animal, the sex and age of the offspring and whether basal or stimulated HPA axis responses are studied. There are also several recent studies showing long-term effects of prenatal stress on basal cortisol levels, or cortisol responses to stress, in humans. The designs of these studies differ considerably, many are small, and the effects on outcome are also varied. There is little evidence, so far, that altered function of the HPA axis in the child mediates the behavioural or cognitive alterations observed to be associated with prenatal stress.

Annual research review: Prenatal stress and the origins of psychopathology: An evolutionary perspective.

If a mother is stressed or anxious while pregnant her child is more likely to show a range of symptoms such as those of attention deficit hyperactivity disorder, conduct disorder, aggression or anxiety. While there remains some debate about what proportion of these effects are due to the prenatal or the postnatal environment, and the role of genetics, there is good evidence that prenatal stress exposure can increase the risk for later psychopathology. Why should this be? In our evolutionary history it is possible that some increase in these characteristics in some individuals was adaptive in a stressful environment, and that this type of fetal programming prepared the child or group for the environment in which they were going to find themselves. Anxiety may have been associated with increased vigilance, distractible attention with more perception of danger, impulsivity with more exploration, conduct disorder with a willingness to break rules, and aggression with the ability to fight intruders or predators. This adaptation for a future dangerous environment may explain why stress and anxiety, rather than depression, seem to have these programming effects; why there is a dose-response relationship with prenatal stress from moderate to severe and it is not only toxic stress that has consequences; why not all children are affected and why individual children are affected in different ways; and why the outcomes affected can depend on the sex of the offspring. An evolutionary perspective may give a different understanding of children in our society with these symptoms, and suggest new directions for research. For example, there is some evidence that the type of cognitive deficits observed after prenatal stress have specific characteristics; these may be those which were adaptive in a past environment.

Prenatal Stress and Neurodevelopment of the Child: Focus on the HPA Axis and Role of the Placenta

Recent human studies have shown that a wide variety of prenatal stressors, from anxiety and partner relationship problems, to natural disasters, increase the risk for a diverse range of adverse neurodevelopmental outcomes in the child. These include impaired cognitive development and behavioral problems, autism and schizophrenia. However, many questions remain about the underlying processes. Much of the research, based on animal studies, has focussed on the maternal HPA axis, with mixed results. Maternal stress or anxiety during pregnancy has been found to be weakly associated with raised maternal cortisol, if at all. The placenta may be a more promising programming vector, because it controls fetal exposure to the maternal environment. Animal studies indicate that prenatal stress can affect the activity of the placental barrier enzyme 11-βHSD2, which metabolises cortisol. We review the evidence for a similar mechanism in humans and how maternal stress may cause other changes in the placenta which affect fetal neurodevelopment.

Fetal plasma cortisol and β-endorphin response to intrauterine needling

Abstract Summary The purpose of this study was to investigate whether the fetus mounts a hormonal stress response to a potentially painful procedure, intrauterine needling. Cortisol and β-endorphin concentrations in fetal plasma obtained during uncomplicated fetal blood sampling or intrauterine transfusions by needling the fetal intra-abdominal portion of the umbilical vein (intrahepatic vein) were compared to hormone concentrations in fetal plasma obtained by the conventional technique of needling the placental cord insertion, which is not innervated. Cortisol and β-endorphin concentrations did not increase within 10 minutes of fetal abdominal needling (n=15). However, more prolonged needling during transfusion at the intrahepatic vein was associated with an increase in fetal plasma cortisol (median increase 48 nmol/L; 95% Cl, 23-86) and β-endorphin (207 pg/mL; 113-307) concentrations compared to transfusion at the placental cord insertion (p These data suggest that the fetus mounts a hormonal stress response to invasive procedures. They raise the possibility that the human fetus feels pain in utero, and may benefit from anaesthesia or analgesia for invasive procedures.

Maternal Prenatal Cortisol and Infant Cognitive Development: Moderation by Infant–Mother Attachment

BACKGROUND Experimental animal studies suggest that early glucocorticoid exposure may have lasting effects on the neurodevelopment of the offspring; animal studies also suggest that this effect may be eliminated by positive postnatal rearing. The relevance of these findings to humans is not known. METHODS We prospectively followed 125 mothers and their normally developing children from pregnancy through 17 months postnatal. Amniotic fluid was obtained at, on average, 17.2 weeks gestation; infants were assessed at an average age of 17 months with the Bayley Scales of Infant Development, and ratings of infant-mother attachment classification were made from the standard Ainsworth Strange Situation assessment. RESULTS Prenatal cortisol exposure, indexed by amniotic fluid levels, negatively predicted cognitive ability in the infant, independent of prenatal, obstetric, and socioeconomic factors. This association was moderated by child-mother attachment: in children with an insecure attachment, the correlation was [r(54) = -.47, p < .001]; in contrast, the association was nonexistent in children who had a secure attachment [r(70) = -.05, ns]. CONCLUSIONS These findings mimic experimental animal findings and provide the first direct human evidence that increased cortisol in utero is associated with impaired cognitive development, and that its impact is dependent on the quality of the mother-infant relationship.