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

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Abstract

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.

Introduction

‘And surely we are all out of the computation of our age, and every man is some months elder than he bethinks him; for we live, move, have a being, and are subject to the actions of the elements, and the malices of diseases, in that other World, the truest Microcosm, the Womb of our Mother’(Sir Thomas Browne, Religio Medici, 1642) [1]

The question of the importance of prenatal environmental factors for development, behaviour and health, has been scientifically studied from the 1940s onwards in humans [1], [2], [3], [4] and even earlier, from the 19th century onwards, in experimental embryology (see [5], [6]). The fetal programming hypothesis states that the environment in utero can alter the development of the fetus during particular sensitive periods, with a permanent effect on the phenotype. In recent years, the work of Barker has given a great impetus to research in this particular field. He proposed “the fetal origins of adult disease hypothesis”. This states that the physiological, neuroendocrine or metabolic adaptations that enable the fetus to adapt to changes in the early life environment result in a permanent programming (or re-programming) of the developmental pattern of proliferation and differentiation events within key tissues and organ systems and can have pathological consequences in later life [7], [8]. The key observation on which this was based was that weight at birth was a strong risk factor for coronary heart disease, diabetes mellitus, and obesity later in life. This finding has been reproduced in many independent studies, although it appears to be the ponderal index rather than birth weight that matters (for reviews see [9] for coronary heart disease; [10] for obesity). Most of the work on the possible mechanisms underlying these findings have focused on nutrition, although there is also evidence that the hypothalamic–pituitary–adrenal (HPA)-axis may be involved [8], [11]. In parallel with this work in humans there has been a strong body of animal research linking prenatal stress and both HPA-axis dysfunction and the underlying neurotransmitter systems, and disturbed behaviour in animal offspring [12], [13], [14], [15]. A consistent finding in the non-human primate work is that stressing the mother during pregnancy has a long-term adverse effect on attention span, neuromotor behaviour, and adaptiveness in novel and stress-inducing situations (e.g. enhanced anxiety) of the offspring [14], [16].

Human studies on the long-term effects of prenatal stress are difficult. In 1893, Dr Alfred W. Wallace (cited in [1]) wrote to Nature: ‘Changes in mode of life and in intellectual occupation are so frequent among all classes, that materials must exist for determining whether such changes during the prenatal period have any influence on the character of the offspring’ ([1] p. 3). Joffe [1] concluded that, in human studies, obtaining sufficient control of genetic and post-natal environmental factors had been the major difficulty to enable the post-natal behavioural differences under investigation to be attributed conclusively to prenatal variables. However, he concluded that even if uncertainty about etiological relationships exists, human studies provide sufficient evidence to enable preventive action to be initiated with regard to a variety of childhood disorders, without waiting for the methodological issues to be unraveled… ‘though the action may be more effective when they are’ ([1] p. 308).

In humans, studies during the last two decades have provided continuing and mounting evidence that negative maternal emotions during pregnancy are associated with an adverse pregnancy outcome. The association between high antenatal anxiety/stress and preterm delivery and low birth weight for gestational age are the most replicated findings and have been discussed fully elsewhere (for recent reviews see [15], [17], [18], [19], [20]). A meta-analysis of 29 studies on work-related stress and adverse pregnancy outcome showed that occupational exposures significantly associated with preterm birth included physically demanding work, prolonged standing, shift and night work, and a high cumulative work fatigue score. Physically demanding work was also related to pregnancy-induced hypertension and preeclampsia [21]. Pregnancy-induced hypertension was shown to be related to Trait Anxiety score (and maternal ponderal index) during the 7th month of pregnancy [22]. Hypertension and preeclampsia in turn, increase the rate of preterm delivery and small-for-gestational-age infants [23]. Hansen et al. [24] have shown that severe life events during pregnancy increased the frequency of cranial–neural-crest malformations 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 (1.3–10.3) for other malformations.

In this paper, we review studies of the past two decades, concurrently or prospectively studying the link between antenatal maternal anxiety/stress on the one hand, and fetal behaviour and later development of the child on the other hand. Evidence for underlying physiological mechanisms in humans and possible effects of stress hormones on prenatal brain development are also reviewed. More specifically, the question is raised whether maternal anxiety, apart from affecting the HPA-axis and limbic system [17], may also affect the development of the prefrontal cortex, which is presumed to underlie behavioural alterations seen in children of mothers who were highly anxious/stressed during pregnancy. Finally, we formulate some suggestions for strengthening further research.

Section snippets

Antenatal maternal stress and anxiety and the human fetus

Reports from the pre-ultrasound era, both anecdotal and semi-scientific (i.e. non-controlled), have suggested that prenatal maternal stress, anxiety, and emotions affect fetal functioning, as evidenced by increased fetal heart rate (FHR) and motility [25]. Ultrasound techniques, enabling FHR monitoring and direct fetal behaviour observation for prolonged periods of time, have for two decades been used in longitudinal and cross-sectional studies of the effects of antenatal maternal anxiety and

Overview of results

Evidence from earlier studies has been largely inconclusive but more recent methodologically improved studies support the notion of an overall relationship between negative maternal emotions during pregnancy and reproductive outcome [25]. The intensity and chronicity (or duration) of antenatal anxiety/stress and lack of appropriate coping mechanisms have been identified as critical factors [55], [56]. A recent review suggests that antenatal maternal stress results in a general susceptibility to

Two physiological mechanisms by which the maternal affective state may affect the fetus in humans

Two mechanisms of transmission of anxiety/stress from mother to fetus in humans have been suggested. One hypothesis is that maternal stress hormones, and in particular, glucocorticoids, are transmitted across the placenta [98]. A second possible mechanism is via an effect on uterine artery blood flow [99], [100].

Stress hormones and the developing fetal nervous system: how are they related to behavioural/emotional regulation problems in infants and children?

There is evidence that complex functions such as behavioural and emotional regulation, are mediated through the prefrontal cortex (PFC). The PFC has many subdivisions and collectively these areas have extensive and reciprocal connections with all sensory systems, cortical and subcortical motor system structures, subcortical arousal and attention functions, and with limbic and midbrain structures involved in affect, memory, and reward [113]. Behavioural functions are not localized in the PFC,

General conclusions

This review shows that there is good evidence for a direct link between antenatal anxiety/stress and fetal behaviour observed by ultrasound from 27 to 28 weeks postmenstrual age onwards. There is also accumulating evidence that there are links between maternal mood during pregnancy and the long-term behaviour of her child. The fact that maternal anxiety/stress during pregnancy is linked with later behaviour, even after controlling for effects of post-natal maternal mood and other relevant

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