Maternal and Fetal Conditions With Consequences for the Fetal Brain

Effects of Diabetes on the Placenta

The normal physiology of pregnancy involves increased oxidative and inflammatory stresses, which play a critical role in embryo implantation and normal placental development. However, in diabetic pregnancies these oxidative and inflammatory pathways are amplified, with subsequent impairment of placental development. In rodent models of maternal hyperglycemia, glucose transporters (especially GLUT2) on the fetal side of the placenta are upregulated; the resulting increase in fetal glucose uptake leads to increased oxidative stress. In addition, the increased glucose uptake through GLUT2 suppresses fetal glucosamine uptake, which is critical for glycosylation-dependent pathways of embryonic development, including neural tube formation. Diabetes also increases release of placental cytokines, such as leptin, tumor necrosis factor-α, and interleukin-6. In gestational diabetes elevated levels of oxidative stress suppress normal placental neurotrophin expression. Neurotrophins play an important role not only in fetal brain development but also in placental development and regulation of placental angiogenesis.

The overarching features of especially the pregestational diabetic placenta are those of significant fetoplacental circulatory impairment, with decreased umbilical venous flow and chronic fetal hypoxia. The placental pathology associated with diabetic pregnancy is influenced by the timing of gestational onset of diabetes, with earlier onset being more associated with structural injury, whereas later-onset gestational diabetes is associated with placental dysfunction. Common placental features include an increased incidence of villous fibrinoid necrosis with fibrin deposition replacing the normal stromal elements, thickened trophoblast basement membranes, villous immaturity, and often prominent chorangiosis (see Chapter 10 ). Nucleated red blood cells, indicative of chronic hypoxia, are commonly increased in the villi. Villous immaturity is associated with an increased diffusion distance between the syncytiotrophoblast surface and the villous capillaries, resulting in impaired nutrient transport. The resulting placental dysfunction and its effect on fetal growth and nutrition likely plays an additive role in the adverse neurological outcomes of diabetic pregnancies.

Maternal Diabetes and the Developing Fetal Nervous System

Diabetes in pregnancy has a broad range of potential adverse effects on the offspring. Broadly speaking, the two major forms of neurological complications of diabetic pregnancies are (1) central nervous system (CNS) malformations and (2) long-term neurodevelopmental, behavioral, and psychiatric complications without overt structural (CNS) anomalies. Poor maternal glycemic control plays a central role in all forms of adverse outcome in the offspring of diabetic pregnancies, although other potential pathophysiologic triggers include hyperinsulinemia, hypoglycemia, or fluctuating blood glucose levels.

The Normal Hypothalamic-Pituitary-Thyroid Axis in Pregnancy

Thyroid hormone is the product of the highly complex hypothalamic-pituitary-thyroid (HPT) axis ( Fig. 11.1 ). As with the HPA axis (discussed later), central control of the HPT arises in the hypothalamic paraventricular nucleus (PVN), which produces thyrotropin-releasing hormone to stimulate the anterior pituitary to release thyroid-stimulating hormone (TSH), which in turn acts on the thyroid gland to secrete thyroid hormone. The thyroid produces primarily the prohormone thyroxine (T4) and, to a lesser extent, tri-iodothyronine (T3). Circulating T4 and T3 exist either bound to proteins or in a free form; free T4 (fT4) and fT3 are capable of crossing membranes by facilitated diffusion across transmembrane protein transporters. In the brain, these transporters are expressed on neuronal membranes, the blood-brain barrier, and the choroid plexus endothelial cells. The T4 prohormone has low physiological activity but is transported rapidly across physiological barriers (such as the placenta and blood-brain barrier); conversely, the highly active T3 hormone is far less capable of crossing between tissues and cells. At both the placenta and blood-brain barrier, there is preferential transport of fT4 over fT3. The T4 prohormone is converted intracellularly by de-iodizing enzymes (DIO1, DIO2, and DIO3, the latter two being active in the fetal brain) (see Fig. 11.1 ). Once across the cell membrane, fT4 is converted to fT3 by DIO2. Depressed activity of the DIO2 isoenzyme by, for example, sustained cortisol elevations in chronic maternal stress might result in “cerebral hypothyroidism” despite normal circulating thyroid levels . Interestingly, tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants lead to activation of the DIO2 enzyme. The active fT3 molecule then attaches to nuclear receptors and in this manner influences expression of a variety of genes.

In summary , the bioavailability of fT3 at the nucleus of fetal brain cells is dependent on maternal iodine sufficiency and thyroid function, transport of T4 across the placenta and blood-brain barrier, presence of activated DIO2 in the cells to convert fT4 to the active fT3, and uptake of fT3 into the nucleus. During normal pregnancy, maternal iodine requirements increase by up to 75%. Despite this, a minority of women take iodine supplements during pregnancy. Therefore it is not surprising that about one-third of pregnant women are at least mildly hypothyroid.

Causes of Abnormal Maternal HPT Axis Function

Hypothyroidism in pregnancy is traditionally defined as an elevation of TSH during gestation and affects 2% to 3% of pregnancies. Overt hypothyroidism is defined as an elevated TSH level with a decreased free T4 level; patients with an elevated TSH but normal free T4 are considered to have subclinical disease, which has, however, been associated with cognitive and psychomotor impairments. As discussed later, these criteria may not consistently identify fetal hypothyroidism.

There are multiple reasons for maternal hypothyroidism in pregnancy, including primary thyroid failure and autoimmune thyroid disease, but by far the most common cause of hypothyroid-related fetal disorders is iodine deficiency and an inability to mount a first trimester surge in fetal T4 . In iodine-deficient regions, both the mother and the fetus might remain hypothyroid the entire pregnancy. The large majority of cases of maternal hypothyroxinemia during pregnancy are due to relative iodine deficiency during the period of increased maternal demand. Another common cause of hypothyroidism during early brain development (discussed elsewhere) is premature birth , with transient hypothyroxinemia due to hypothalamic immaturity at a time when maternal thyroid hormone is no longer available; this scenario has been associated with abnormal cognitive outcomes.

External endocrine disruptors are widespread environmental chemicals, such as bisphenol A, that have endocrine-mimicking properties and may interfere with thyroid signaling and result in maternal hypothyroidism. Other rarer causes of maternal hypothyroidism include autoimmune and infectious thyroiditis and are discussed elsewhere. Genetic mutations in thyroid receptors and transporters are extremely rare but include an X-linked mutation of the gene SLC16A2 , which encodes the monocarboxylate 8 (MCT8) transporter proteins that transport T3 into neurons. The resulting Allan-Herndon-Dudley syndrome is characterized by hypotonia and feeding difficulties in infancy, developmental delay and intellectual disability, later-onset pyramidal and extrapyramidal findings, refractory seizures, and severely delayed myelination on magnetic resonance imaging (MRI).

Normal Thyroid Hormone Pathways and Development of the Fetal HPT Axis

Maternal-to-fetal transfer of thyroid hormone extends across all of gestation, but prior to midgestation this transfer is the only fetal source. During early gestation, three interacting pathways unfold, namely, maternal thyroid production increases to support pregnancy, fetal thyroid production is not yet developed, and fetal brain development is critically dependent on thyroid hormone support. Maternal thyroid hormone production increases rapidly after the onset of pregnancy, significantly increasing her iodine requirements.

During the early stages of brain development, adequate fetal fT4 levels are critical for brain development because circulating fT3 levels (even if normal) do not contribute to brain fT3 levels, and virtually all brain intracellular fT3 is generated in situ. During the normal early gestation period, there is an initial transient surge in fT4 in the fetal circulation well before fetal thyroid production begins. This surge in fT4 results from maternal thyroid activation by rising maternal human chorionic gonadotrophin production, which has significant TSH-like activity (see Fig. 11.1 ). This surge in maternal-to-fetal T4 transfer occurs prior to the normal estrogen-activated increase in circulating fetal thyroxine-binding globulin (T4 carrier) levels ; as a result, more fT4 is available to fetal tissues, including the brain. Under these conditions, both maternal TSH and T3 may remain normal, even if circulating maternal, and hence fetal, T4 is inappropriately low or high. This situation presents one of the challenges in assessing fetal T4 levels based on circulating maternal measures.

In experimental models, both fT4 and fT3 are present in fetal tissues well before the fetal thyroid commences production. Although circulating fetal T3 levels remain low throughout gestation, the fetal thyroid begins producing T4 around 12 weeks gestational age (GA), increasing production until 36 weeks GA, when circulating fetal T4 levels reach maternal levels. In the human fetal brain, thyroid hormone transporter mRNA is detectable as early as 8 weeks GA, and its protein product is present at 10 weeks GA. In human fetuses, thyroid hormone receptors in the nuclei of cortical cells are present as early as 8 to 9 weeks and increase 10-fold over the next 18 weeks. Taken together, this series of events results in a dramatic increase in sensitivity of the human fetal brain to thyroid hormonal stimulation after 10 weeks GA .

Thyroid hormone transporters are important for moving fT4 and fT3 across physiological barriers, such as the placenta and blood-brain barrier ( Fig. 11.2 ). Transmembrane transport of fT4 is considerably more efficient than that of fT3. The organic anion transporter polypeptide (OATP1C1) is encoded by the SLCO1C1 gene and has much greater affinity for T4; this transporter is present at the blood-brain barrier and in the astrocytic end-feet, facilitating direct transport from the circulation to astrocytes where fT4 is activated to fT3. The latter is then shunted by secondary transporters into neurons. The MCT8 transporter has affinity for both fT4 and fT3 and appears in the human fetal brain as early as 7 to 8 weeks GA.

Intracellular fT3 levels are tightly controlled by a set of deiodinase enzymes (see Fig. 11.2 ). The type 2 (DIO2) and type 3 (DIO3) deiodinase isoenzymes are relevant to the fetal brain. The DIO2 isoenzyme is responsible for increasing intracellular conversion of circulating fT4 to active fT3. In the developing brain the DIO2 isoenzyme is located primarily in astrocytes but also in some interneurons and oligodendrocyte precursors. Conversely, DIO3 is expressed primarily in neuronal membranes and is responsible for preventing maturationally inappropriate increases in intraneuronal T3 by converting both T4 and T3 to the inactive reverse T3. In this manner, DIO3 regulates the concentration of T3 and T4 and limits the effect of T3 excess on gene expression. Approximately 80% of brain T3 is produced in situ by DIO2. Within human fetal brain cells, an increase in DIO2 expression and a coinciding decrease in DIO3 expression (increasing active intracellular T3) occur in different brain regions over different periods of development. For example, during the second trimester period of increased cortical DIO2 expression and increased T3 in the cerebral cortex, the T3 levels remain suppressed in the cerebellum, basal ganglia, brainstem, and spinal cord because of prolonged high levels of D3 expression in these regions.

In summary , an early gestation T3 surge in the fetal cortex is critical for its normal development and results from a series of physiological events, including human chorionic gonadotrophin stimulation of the maternal thyroid gland, increased transfer of maternal fT4 across the placenta into the fetal circulation, appropriate transport across the blood-brain barrier, and appropriate activation of intracellular DIO2 to provide T3 to the nuclear receptors. Disturbances at any point along this pathway could occur without being reflected in elevated maternal TSH, a commonly monitored index in pregnancy.

Thyroid Hormone’s Role in Normal and Abnormal Fetal Brain Development

Thyroid hormone plays important roles in fetal brain development throughout gestation. During earlier gestation it promotes major events such as neuronal proliferation, differentiation, and migration, and after midgestation it influences axonal and neurite outgrowth and guidance, synaptogenesis, and myelination.

During early gestation (between the 10th and 20th weeks GA) the surge in thyroid hormone activity in the fetal brain, including increases in cortical T3 levels, nuclear T3 receptors, and DIO2 activity, is critical for subsequent development; even mild, transient disturbances of fetal hypothyroidism may lead to persistent brain changes. These normal developmental events are directed by genes regulated by intracellular T3; at this stage of brain development, such genes are maximally expressed in Cajal-Retzius cells of cortical layer 1, subplate neurons, and extracellular matrix proteins, all of which play critical roles in neuronal migration and cortical development (see Chapters 6 and 7 ). In rodent models of gestational hypothyroidism, reduced proliferation of progenitor cells and decreased cortical thickness have been described, as well as disorganized cortical lamination, abnormal neuronal migration, and connectivity. The normal role of thyroid hormone in neuronal migration and axonal guidance is mediated in part through its regulation of Reelin expression by Cajal-Retzius cells. Decreased Reelin expression likely underlies the cerebral and cerebellar neuronal migration anomalies, such as heterotopias in the cerebrum in the callosal and subcortical white matter, seen in offspring even after moderate, transient maternal hypothyroidism. Hypothyroidism in rodent models results in inhibition of maturational pathways in the subplate zone with permanent effects on the cytoarchitecture of the neocortex and hippocampus, including heterotopic neurons in the subcortical white matter. Similar heterotopic neurons have been described in other studies and were thought to reflect abnormal radial migration of cortical neurons or possibly abnormal tangential migration of neurons from the medial ganglionic eminence. In human neuropathology studies, such interstitial white matter neurons, thought to be residual subplate neurons, have been described in such neurodevelopmental disorders as schizophrenia and autism.

A number of experimental studies have suggested an important role for thyroid hormone in development of the fetal gamma-aminobutyric acid (GABA) neurotransmitter system . Specifically, maternal hypothyroidism is associated with a significant decrease in GABAergic interneurons and their axonal and dendritic processes, as well as disturbances in their tangential migratory path from the medial ganglionic eminence. One pathway through which thyroid hormone influences various facets of fetal brain development, including maturation of the GABAergic system and oligodendrocyte precursors, involves increased expression of various neurotrophins. Several studies have suggested that fetal hypothyroidism disrupts development of the GABAergic system by disturbing the normal switch of GABA from an excitatory-to-inhibitory neurotransmitter (E/I switch). During early brain development, GABA functions as an excitatory neurotransmitter, switching to an inhibitory role after the perinatal-neonatal period. Disturbances in this E/I switch have been linked to a number of adverse outcomes, including autism spectrum disorder (ASD) and schizophrenia, conditions associated with gestational hypothyroidism in humans (discussed later). The functional E/I GABA switch is thought to be triggered by a maturational increase in expression of the neuronal chloride cotransporter KCC2. The expression of KCC2 expression is upregulated by brain-derived neurotrophic factor, which is in turn upregulated by thyroid hormone. In this manner, fetal hypothyroidism may disrupt the normal maturation of the GABA E/I switch, thereby perhaps predisposing to future neurodevelopmental sequelae such as ASD .

Thyroid hormone also plays an important role in cerebellar development . The developing cerebellum goes through a complex series of maturational events to achieve its foliation and cortical layering patterns, discussed in Chapter 4 . Sonic hedgehog (Shh) expression by Purkinje cells is a potent stimulator of cerebellar granule cell proliferation and plays a major role in cerebellar development. In a rodent model, gestational hypothyroidism suppressed the expression of the Shh pathway and granule cell proliferation. In other such models, disturbances in Purkinje and granule cell differentiation, abnormal dendritic development, and decreases in cerebellar gene expression have been described.

Thyroid hormone also plays an important role in myelination by promoting maturation of the oligodendrocyte lineage through increased expression of T3-dependent neurotrophin, resulting in increased myelin protein expression, especially myelin basic protein. In experimental models of maternal hypothyroidism the offspring have delayed myelination and reduced white matter volumes, with a significantly reduced number of myelinated axons in major white matter tracts, such as the corpus callosum.

Neurological and Developmental Consequences of Abnormal Fetal Thyroid Hormone Metabolism

Newborn infants with primary congenital hypothyroidism who are diagnosed early and treated promptly with thyroid hormone replacement tend to have favorable outcomes, presumably because maternal thyroid hormone can support fetal brain development. This observation led to an earlier notion that thyroid hormone was of little consequence in the fetal period and could be corrected after birth without permanent sequelae. This concept has been thoroughly disproved by a large body of experimental (discussed earlier) and human evidence. A recent meta-analysis found that maternal hypothyroidism in pregnancy was associated with a three-fold increase in impaired cognitive development in the offspring . These adverse effects of maternal hypothyroidism on cognitive and neurodevelopmental outcomes of their offspring have also been described in other studies. A large systematic review recently concluded that maternal hypothyroidism, even when subclinical, is associated with long-term intellectual disability but not attention deficit hyperactivity disorder (ADHD). In another study, Modesto et al. found maternal hypothyroidism in early pregnancy to be an independent risk factor for ADHD. In a large prospective Danish study, maternal hypothyroidism in pregnancy was associated with an increased risk of epilepsy, autism spectrum disorder, ADHD, and psychiatric disorders , including schizophrenia. An increase in ASD following gestational hypothyroidism has also been described in other studies.

Not surprisingly, the association between hypothyroidism during pregnancy and the profile of neurological impairment in the offspring is influenced by the onset and duration of thyroid hormone deficiency . This association is strongest earlier in gestation when failure of the late first trimester surge in maternal fT4 occurs before the onset of fetal thyroid production. During these earlier stages of brain development, even small or subtle alterations in brain structure or function may lead to progressive disruption of future events in brain development, resulting in long-term functional impairments that are no longer reversible by late pregnancy or neonatal thyroid hormone replacement.

As discussed earlier, fetal levels of thyroid hormone are maintained, at least in part, by maternal supply throughout gestation until delivery. This sustained need for maternal thyroid hormone support is a concern when preterm infants are prematurely separated from maternal thyroid hormone supply and potentially exposed to a transient period of hypothyroidism . Though data concerning the adverse effects of early gestation maternal hypothyroidism on fetal brain development are compelling, support for such effects is less so for the later stages of gestation. In the fetus with primary congenital hypothyroidism, failure of the expected increase in thyroid hormone production in the late first trimester may result in insufficient thyroid hormone support of the rapid brain development in the third trimester. Normal developmental events in the fetal brain during the later stages of gestation include axonal outgrowth and connectivity, dendritic arborization and pruning, synapse formation, and early myelination. The range of neurological sequelae usually associated with disruption of these late events is broad but includes long-term deficits in memory, language, sensory processing, and attentional and executive dysfunction, deficits that have been described after gestational hypothyroidism.

There is a lack of consensus about whether maternal hypothyroidism (especially mild) that remains uncorrected after fetal production is established is associated with adverse neurodevelopmental outcome and whether maternal supplementation during the later periods of gestation is effective. In an earlier report, the risk for impaired neurodevelopmental outcome in offspring was significantly increased when low maternal thyroid levels were detected at 12 weeks GA but not when identified at 32 weeks GA. Although the human outcome data for the adverse neurodevelopmental outcomes of maternal hypothyroidism after midgestation are less compelling than those for earlier stages of pregnancy, there is a growing body of experimental data from models of late maternal hypothyroidism (discussed earlier) that support its adverse effect on brain development.

Hyperthyroidism in Pregnancy

Given the multiple roles and pathways of thyroid hormone in normal brain development (discussed earlier), hyperthyroidism might be expected to have significant adverse effects on the fetal brain. Maternal hyperthyroidism in pregnancy is far less common than hypothyroidism; in the form of Graves disease it affects 0.05% to 0.2% of pregnancies, and a further 2% to 3% of pregnancies are complicated by transient gestational thyrotoxicosis. The risks to the fetus of mothers with Graves disease are related to both the maternal disease and its treatment . Fetal hyperthyroidism may develop because of placental transfer of maternal T3/T4 and anti-TSH autoantibodies, particularly after midgestation; conversely, fetal hypothyroidism may result from excessive exposure to maternal antithyroid medications. Fetal thyrotoxicosis, which is most commonly diagnosed in the third trimester, is marked by tachycardia and may be complicated by fetal growth restriction, fetal hydrops, organomegaly, and craniosynostosis. The effects on the fetal brain may be direct or secondary to maternal complications with elevated risk to the fetal brain, such as hypertension, preeclampsia, intrauterine growth restriction, and preterm birth. In the newborn, persistent thyroid stimulation by maternally generated antibodies may lead to neonatal thyrotoxicosis with significant morbidity and mortality.

Unlike data on hypothyroidism, information on the effects of maternal hyperthyroidism on the developing fetal brain and its long-term functional outcome is scarce and for the most part less than compelling. In one report of 31 cases born to mothers with Graves disease, there was no significant difference in total, verbal, or performance IQ skills at a median age of 11 years compared with controls. All cases had been treated with maternal antithyroid drugs and were euthyroid at birth. These results were similar to those from two other reports. A recent systematic review and meta-analysis found an association between hyperthyroidism and ADHD, ASD, and epilepsy in the offspring, although the effects were modest at best. Thus, in summary, the data for an association between maternal hyperthyroidism in pregnancy and offspring neurodevelopmental outcomes are scarce and inconsistent .

Maternal Stress, Depression, and the HPA and HPT Axes

Both glucocorticoid and thyroid hormones play major roles in fetal tissue maturation, including that of the fetal brain. During gestation the HPA and HPT axes interact at multiple levels to regulate and counterregulate each other; both glucocorticoid and thyroid hormone levels increase prior to and during the intrapartum period. Sustained low levels of thyroid hormone and elevated glucocorticoid levels have adverse effects on fetal brain development.

The HPT and HPA axes are also part of the stress response system, and sustained activation of this system is known to have multiple adverse effects on fetal development and long-term outcome (see later). During acute stress the HPT axis activity decreases, possibly as an energy-conserving mechanism in threatening situations; however, acute stress also increases DIO2 activity in the brain, leading to increased intracellular active T3. During chronic stress and glucocorticoid treatment the HPT axis is suppressed, likely at multiple levels, including decreased circulating TSH as well as decreased DIO2 activation, by chronically increased cortisol levels. Given the fetal exposure to chronically elevated cortisol levels during maternal mental health disorders in pregnancy (see later), the potential effect of “cerebral hypothyroidism” in the developing fetal brain is of interest. The fact that DIO2 activity has been shown to be enhanced by certain agents (e.g., tricyclic antidepressants and SSRIs), thereby increasing intracellular T3 in the brain, might make DIO2 a potential future therapeutic target. In adults, glucocorticoids generally inhibit thyroid function, though recent data from ovine models suggest that the reverse response may occur during fetal development. Hypothyroidism decreases the inactivation of cortisol to cortisone possibly through decreased activation of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), thereby further exposing the fetal brain to cortisol (discussed later).

Development of the Fetal HPA Axis

The maternal-placental-fetal cortisol pathways are complex (see Fig. 11.3 ). Although the fetal adrenal gland is active from early gestation, fetal cortisol production remains low until midgestation. During early gestation the fetus is primarily dependent on maternal cortisol levels (as is the case with thyroid hormone); thereafter circulating levels of fetal cortisol rise steadily throughout pregnancy, under tight regulatory control, to prepare for parturition and to ensure appropriate fetal maturation for extrauterine life (see earlier). The increasing fetal cortisol levels are due to several factors, including increasing fetal adrenal production, increasing CRH production by the placenta, and decreased expression of placental 11β-HSD, which decreases the inactivation of maternal cortisol. These changes begin in the second trimester and increase across gestation, surging over the final 6 to 8 weeks.

There are a number of important genes involved in the glucocorticoid pathways in and between the mother, placenta, and fetus, including the fetal brain. These genes, which include HSDB2, FKBP5 , and NR3C1 , are potential targets for epigenetic mechanisms that may lead to dysregulation of the HPA axis. The NR3C1 gene encodes the glucocorticoid receptor. The FKBP5 gene encodes a molecular binding protein chaperone of glucocorticoid receptor regulation. FKBP5 is a cochaperone protein that forms a complex with the glucocorticoid receptor. When FKBP5 is attached to the inactive receptor the affinity for glucocorticoids is reduced. The HSDB2 gene encodes the placental barrier enzyme 11β-HSD-2 and is expressed in the syncytiotrophoblast, where it converts bioactive cortisol to its inert metabolite, cortisone. By the 16th week GA, the placental enzyme 11β-HSD-2 forms a barrier to maternal glucocorticoids. Of note, exogenous GCCs (betamethasone and dexamethasone) are not inactivated by 11β-HSD and do not bind to corticosteroid-binding globulin. During normal pregnancy, 11β-HSD-2 maintains a transplacental cortisol gradient with circulating maternal levels 5- to 10-fold higher than fetal levels. In this manner, 11β-HSD-2 limits exposure of the developing fetus to the downstream effects of maternal cortisol. By regulating fetal cortisol exposure, placental 11β-HSD-2 also plays an important role in regulation of fetal growth. However, 10% to 20% of maternal cortisol does pass through the placenta to the fetus, and under conditions of stress this exposure can become excessive . Toward term gestation the barrier function of 11β-HSD-2 decreases, presumably to allow the physiological increase in fetal cortisol required for late gestation fetal maturation and preparation for approaching labor. By term gestation, 75% of fetal cortisol is of fetal adrenal origin, whereas all fetal cortisone is maternal in origin. Importantly, exogenous synthetic glucocorticoids, such as dexamethasone and betamethasone, administered to advance lung maturation in cases of imminent premature delivery are not well metabolized by placental 11β-HSD-2 . A number of pregnancy complications may compromise the barrier function of placental 11β-HSD-2, including placental dysfunction with syncytiotrophoblast injury.

The Stress Response System

The HPA axis plays a number of physiological roles, one of which is to combine with the autonomic nervous system as part of the neuroendocrine stress response system. This system is activated by different forms of stress, acute or chronic. Concerning acute stress , so-called “processive” stressors include fear or perceived threat and operate through higher-order sensory processing through the limbic system to activate the PVN (the hypothalamic source of CRH). “Systemic” stressors are physiological stressors with life-threatening implications, such as hypoxia and hypotension; these do not involve limbic pathways but are relayed rapidly and directly by excitatory visceral efferent pathways from the brainstem to the PVN without cognitive processing. The escalation of cortisol levels during acute stress activates centers in the limbic system, especially the hippocampus and amygdala, which have a particular abundance of glucocorticoid receptors; these centers then exert positive and negative feedback on the HPA axis. Specifically, activation of hippocampal glucocorticoid receptors triggers polysynaptic inhibitory neural feedback at the PVN. The initial step occurs through excitatory input to the bed nucleus of the stria terminalis (BNST), a convergence site and integrator for many stress pathways. The BNST connects limbic structures, such as the amygdala and hippocampus, to the homeostatic centers in the hypothalamus and brainstem. After activation by the hippocampus, the BNST projects GABAergic input to the PVN, inhibiting CRH and ACTH release and restoring cortisol to baseline (see Fig. 11.3 ). Other regions, such as the prefrontal cortex, may also have inhibitory neural pathways to the PVN. In contrast to the hippocampus, the cortisol-activated amygdala acts through the BNST to stimulate the hypothalamic PVN, further elevating fetal cortisol levels. Acute homeostatic stressors, such as hemorrhage, hypoxia, and hypotension, activate catecholaminergic pathways from the brainstem, projecting to the PVN where they stimulate the HPA axis. The stress axis may also be activated by noradrenergic afferents from the brainstem locus coeruleus and serotonergic afferents from the brainstem raphe nuclei.

The above neuroendocrine integration loops apply to acute stress. During chronic stress , sustained elevation of cortisol induces changes in neuronal integrity and function in the fetal hippocampus and hypothalamus, thereby reprogramming the fetal HPA axis set point. Sustained elevations of cortisol lead to a reduced hippocampal glucocorticoid receptor expression and sensitivity ; this in turn decreases negative feedback control to the hypothalamus, thereby sustaining increased cortisol production.

In excess, cortisol may become toxic to the fetus along multiple pathways, including dysfunctional patterning of the HPA axis and disruption of normal brain development . The ubiquitous distribution of glucocorticoid receptors throughout the brain may underlie the broad spectrum of adverse neurodevelopmental and neuropsychologic outcomes associated with elevated fetal cortisol levels . In addition, disturbed programming of the fetal HPA axis may result in excessive reactivity to stress across the life span . In animal models, high levels of fetal cortisol results in changes in fetal hippocampal development, with sustained decreases in hippocampal volume. In humans, repeated doses of antenatal betamethasone have been associated with significantly lower cortical surface area and gyral formation, particularly when steroids are administered during the late gestation burst of cortical development. Together, the changes induced by chronic elevation of cortisol may lead to enduring dysregulation of the central neuroendocrine stress response circuitry, resulting in exaggerated cortisol reactivity and potentially lifelong neurobehavioral and metabolic risks. Dysregulation of stress pathways is a common feature of most neuropsychiatric diseases. The hippocampus is especially stress sensitive, and disturbances in hippocampal function are thought to play a role in various forms of psychiatric illness. Excessive reactivity of the HPA axis is common in depression, with elevated ACTH and cortisol levels. Responses to elevated glucocorticoid levels in the placenta and fetus, including the fetal brain, are sexually dimorphic, and these may underlie the different manifestations in male and female offspring. For example, first trimester exposure to stress is a significant risk factor for schizophrenia in males but not in females.

In summary , chronic elevation of maternal and fetal cortisol levels may be a final common pathway to neuropsychiatric sequelae in the offspring of complicated pregnancies. The disruptive effects on fetal brain development of sustained cortisol elevation have the potential to disrupt the programming of the neuroendocrine system in profound ways, leaving the offspring at elevated risks of lifelong metabolic and neuropsychiatric morbidity.