Long-term follow-up in pediatric intensive care-a narrative review.

Pediatric intensive care is a rapidly developing medical specialty and with evolving understanding of pediatric pathophysiology and advances in technology, most children in the developed world are now surviving to intensive care and hospital discharge. As mortality rates for children with critical illness continue to improve, increasing PICU survivorship is resulting in significant long-term consequences of intensive care in these vulnerable patients. Although impairments in physical, psychosocial and cognitive function are well documented in the literature and the importance of establishing follow-up programs is acknowledged, no standardized or evidence-based approach to long-term follow-up in the PICU exists. This narrative review explores pediatric post-intensive care syndrome and summarizes the multifactorial deficits and morbidity that can occur in these patients following recovery from critical illness and subsequent discharge from hospital. Current practices around long-term follow-up are explored with discussion focusing on gaps in research and understanding with suggested ways forward and future directions.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

Prenatal intimate partner violence exposure predicts infant biobehavioral regulation: Moderation by the brain-derived neurotrophic factor (BDNF) gene.

The ability to regulate stress is a critical developmental milestone of early childhood that involves a set of interconnected behavioral and physiological processes and is influenced by genetic and environmental stimuli. Prenatal exposure to traumatic stress and trauma, including intimate partner violence (IPV), increases risk for offspring biobehavioral regulation problems during childhood and adolescence. Although individual differences in susceptibility to prenatal stress have been largely unexplored, a handful of studies suggest children with specific genetic characteristics are most vulnerable to prenatal stress. We evaluated the brain-derived neurotrophic factor Val66Met gene (BDNF) as a moderator of the effect of prenatal IPV exposure on infant temperamental and cortisol regulation in response to a psychosocial challenge. Ninety-nine mother-infant dyads recruited from the community were assessed when infants (51% female) were 11 to 14 months. Maternal reports of IPV during pregnancy and infant temperament were obtained, and infant saliva was collected for genotyping and to assess cortisol reactivity (before and after the Strange Situation Task). Significant genetic moderation effects were found. Among infants with the BDNF Met allele, prenatal IPV predicted worse temperamental regulation and mobilization of the cortisol response, while controlling for infant postnatal exposure to IPV, other maternal traumatic experiences, and infant sex. However, prenatal IPV exposure was not associated with temperamental or cortisol outcomes among infant carriers of the Val/Val genotype. Findings are discussed in relation to prenatal programming and biological susceptibility to stress.

Immune and neuroendocrine correlates of temperament in infancy.

There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.

Maternal abuse history and reduced fetal heart rate variability: Abuse-related sleep disturbance is a mediator.

The consequences of childhood maltreatment are profound and long lasting. Not only does the victim of abuse suffer as a child, but there is mounting evidence that a history of maltreatment places the next generation at risk for significant psychopathology. Research identifies postnatal factors as affecting this intergenerational transmission of trauma. However, emerging evidence suggests that part of this risk may be transmitted before birth, passed on via abuse-related alterations in the in utero environment that are as yet largely unidentified. To date, no study has directly assessed the influence of pregnant women's abuse history on fetal neurobehavioral development, nor considered trauma-associated poor sleep quality as a mediator reflecting established physiological dysregulation. Using data from 262 pregnant adolescents (ages 14-19), a population at elevated risk for childhood maltreatment, the current study examined maternal emotional abuse history and sleep quality in relation to third-trimester fetal resting heart rate variability, an index of parasympathetic nervous system functioning. The results indicate that maternal emotional abuse history is indirectly associated with lower fetal heart rate variability via abuse-related sleep disturbances. These data demonstrate an association between maternal abuse histories and fetal development, showing that at least part of the intergenerational transmission of risk occurs during pregnancy.

The Effects of Trauma History and Prenatal Affective Symptoms on Obstetric Outcomes.

Prenatal maternal mood may inform the adverse obstetric outcomes seen in disadvantaged populations. The contribution of having a trauma history is not well studied. We examined the impact of trauma exposure and mood symptoms on obstetric outcomes in 358 women. Women with antecedent trauma were more likely to have a history of depression, odds ratio = 2.83, 95% confidence interval [1.81, 4.42], were younger at their first pregnancy, 18.86 years versus 20.10 years, and had a higher number of previous pregnancies, 2.01 versus 1.54, compared to those with no trauma exposure. Women with prenatal anxiety had significantly smaller babies than nonanxious women, 3,313.17 g, (SD = 441.58) versus 3,429.27 g, (SD = 437.82) Trauma history magnified the effects of maternal prenatal mood on birthweight; the moderating effect was limited to those who first experienced a trauma under 18 years of age. Childhood trauma exposure increased vulnerability for low birthweight delivery associated with prenatal mood disturbance. Screening pregnant women for trauma history and current mood symptoms is indicated.

Associations Among Child Abuse, Depression, and Interleukin-6 in Pregnant Adolescents: Paradoxical Findings.

OBJECTIVE: Limited data exist on child abuse-related immune variation during pregnancy, despite implications for maternal and infant health and extensive data showing that abuse history and depression are related to increased inflammation in other populations. This study examined associations among child abuse, depression, circulating levels of inflammatory markers, and perinatal health in pregnant adolescents, a group at high risk for childhood abuse and poor birth outcomes. METHODS: Pregnant teenagers (n = 133; 14-19 years; 89.5% Latina) reported on abuse and depression and had two blood draws (24-27 and 34-37 gestational weeks, second and third trimesters, respectively) for interleukin-6 (IL-6) and C-reactive protein; birth outcomes were collected. RESULTS: Abuse and depression interacted to predict higher IL-6 at second trimester (B = 0.006, p = .011) such that severely abused adolescents with high depression had higher IL-6 relative to severely abused adolescents with low depression; depression did not differentiate IL-6 levels for those with low abuse severity. Abuse and IL-6 also interacted to predict gestational age at birth (B = 0.004, p = .040) such that those with low abuse and high IL-6 and those with high abuse and low IL-6 had infants with earlier gestational age at birth. Cortisol at the second trimester mediated the association between IL-6 and gestational age at birth (indirect effect estimate=-0.143, p < .039). CONCLUSIONS: Depression severity distinguished IL-6 levels among more severely abused pregnant Latina adolescents, but it was unrelated to IL-6 among less severely abused adolescents. Cortisol explained the relationship between IL-6 and earlier gestational age at birth. Multiple adversities and inflammation may influence birth outcomes and potentially affect intergenerational health.

Pregnancy-related anxiety: Evidence of distinct clinical significance from a prospective longitudinal study.

BACKGROUND: Pregnancy-related anxiety (PrA) has attracted considerable research attention, but questions remain about its distinctiveness from conventional constructs and measures. In a high psychosocial risk, ethnically diverse sample, we examine the degree to which PrA is distinct from continuous and diagnostic measures of anxiety and worry in terms of longitudinal course, associations with psychosocial and perinatal risk, and prediction of postnatal mood disturbance. METHODS: 345 women oversampled for prenatal anxiety and depression were selected from an urban obstetrics clinic serving a predominantly low-income, ethnically diverse population. PrA was assessed at 20 and 32 weeks gestation; anxiety and depression symptoms were assessed from questionnaire and from clinical interview at 20 and 32 weeks gestation and again at 2 and 6 months postnatally. Data relevant to psychosocial and obstetric risks were ascertained from interview, medical exam, and chart review. RESULTS: Two distinct factors of PrA were identified, indexing specific concerns about the child's health and about the birth; these two PrA factors showed distinct longitudinal patterns in the prenatal period, and modest associations with general measures of anxiety and depression from questionnaire and clinical interview. PrA was also distinguished from conventional symptom measures in its associated features and prediction of birth weight and postnatal mood. LIMITATIONS: The sample was at high psychosocial risk and ethnically diverse; findings may not generalize to other samples. CONCLUSIONS: PrA can be distinguished from general measures of anxiety in pregnancy in terms of longitudinal course, associated features, and prediction to postnatal mood disturbance, and may warrant specific clinical attention.

Diurnal cortisol patterns and psychiatric symptoms in pregnancy: short-term longitudinal study.

Alteration in the HPA axis is a robust biomarker of anxiety and depression in adults, but questions remain about this association in pregnancy. We examined the longitudinal links between diurnal cortisol and mood symptoms from self-report questionnaire and diagnostic interview in an ethnically diverse, psychosocially at-risk sample of 101 women at mid-pregnancy and early third trimester. There were modest but significant associations between depression and elevated cortisol, indexed by a decreased morning level and diminished diurnal decline; the effects were strongest for diagnostic data from clinical interview. These effects were independent of socio-demographic factors and sleep disturbance. Associations with anxiety and trauma were generally non-significant. These findings extend prior work by showing that significant mood symptoms in pregnancy are associated with altered diurnal cortisol in pregnancy, which may have implications for maternal and child health.

Depressive symptoms and proinflammatory cytokines across the perinatal period in African American women.

BACKGROUND: Comparatively few studies have examined the biological mechanisms that may underlie the reported racial disparities in antenatal and postpartum depression. OBJECTIVE: To examine the associations among race, depressive symptoms and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α across the perinatal period in a diverse sample of healthy pregnant women at elevated psychosocial risk. METHODS: 171 subjects were enrolled. Women were interviewed and blood samples drawn at 18 and 32 weeks gestation and 6 weeks and 6 months postpartum. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Serum levels of IL-6 and TNF-α were assayed using high sensitivity enzyme-linked immunosorbent assay kits. RESULTS: Compared with non-African American (AA) women, AA women had significantly higher levels of IL-6 (est. diff = 0.521, p = 0.02, confidence interval (CI): 0.088-0.954) but not TNF-α across all time points (est. diff = -0.060, p = 0.80, CI: -0.517 to 0.397). IL-6 was not associated with depressive symptoms but differences in IL-6 were accounted for by greater Body Mass Index in AA women. CONCLUSIONS: Compared with non-AA women, AA women entered pregnancy with elevated inflammatory cytokine levels that persisted across the perinatal period. This group difference in inflammation did not suggest increased risk for depression, but suggests other implications for long-term health.

An unusual cause of fever.

A 5-month old infant presented with a short history of fever of unknown origin. He initially appeared well although there was a resting tachycardia during periods of normal temperature, and pancytopenia. He remained febrile in spite of antibiotic therapy and by 48 h he had developed marked hepatosplenomegaly and coagulopathy. At 72 h a bone marrow aspirate and trephine biopsy showed haemophagocytosis. By this time the infant was encephalopathic and haemodynamically unstable with multi-organ dysfunction. Treatment with high-dose methylprednisolone and cyclosporin was commenced with an initial good response. Unfortunately the patient ultimately died of infective complications of treatment and reactivation of the underlying disease process. Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the mononuclear phagocyte system characterised by proliferation of morphologically benign histiocytes resulting in hypercytokinaemia and uncontrolled activation of immune cells. The diagnosis of familial HLH should be considered in any infant with fever, splenomegaly and cytopenia of at least two cell lines. HLH may be cured by immunosuppressive therapy and eventual stem cell transplantation but rapid disease progression to multi-organ failure results in a high mortality.

Psychiatric symptoms and proinflammatory cytokines in pregnancy.

OBJECTIVE: Clinical studies suggest that psychiatric symptoms, particularly depression, anxiety, and trauma, may be associated with inflammation, as indexed by proinflammatory cytokines. Such a link may be especially significant in pregnancy and may shed additional light on the etiology of perinatal mood disorders. METHODS: We prospectively observed 145 women selected from a community obstetric clinic serving a primarily low-income, high-psychosocial risk population. Women without evidence of medical high-risk pregnancies were screened (including psychiatric and trauma histories) and then assessed in detail (e.g., mood symptoms) at approximately 18 and 32 weeks' gestation. Blood was drawn to measure key proinflammatory markers, interleukin 6 and tumor necrosis factor α (TNF-α). Data on pregnancy and obstetric outcome were derived from medical records. RESULTS: There was considerable stability of cytokine levels within individuals and a significant mean increase across pregnancy observed for interleukin 6 (p < .001) and TNF-α (p < .001). History of trauma was associated with significantly elevated TNF-α levels (F(1,135) = 4.43, p < .05), controlling for psychosocial and obstetric covariates. In contrast, elevated measures of depression and anxiety were unrelated to proinflammatory cytokines (p > .1). Exploratory analyses indicated that neither psychiatric symptoms nor proinflammatory cytokines predicted birth weight, gestational age, or obstetric complications. CONCLUSIONS: These findings suggest that antecedent trauma may be associated with persistently elevated TNF-α levels during pregnancy. The evidence that a generalized proinflammatory state was associated with symptoms of depression or anxiety in pregnant women was not found.