Internet-based interdisciplinary therapeutic group (Grupo Interdisciplinar Online, GIO) for perinatal anxiety and depression-a randomized pilot study during COVID-19.

Early interventions may promote reductions in mothers' anxiety-depression (AD) symptoms and improvements in their offspring. This longitudinal randomized research was conducted to assess the effects of interdisciplinary online therapeutic groups (GIO) in at-risk mothers and babies during the COVID-19 pandemic in a disadvantaged neighborhood in Barcelona (Spain). A total of 135 babies were born from March 2020 to June 2021 in a primary healthcare center of Barcelona (Spain). Pregnant woman and new mothers were screened for AD symptomatology through EPDS and STAI questionnaires. Seventy-two of them met high-risk criteria for AD and were included in the study. They were randomly assigned into the two groups of the study: 40 participants were assigned to GIO, the therapeutic group (TG), while 32 of them were assigned to the control group (CG) and received treatment as usual. The course of the mothers' symptomatology was assessed, as well as the baby's development at 6 months old in a blind pediatric follow-up. No differences were found in AD between both groups before the intervention. However, we obtained a significant decrease in AD symptomatology (EPDS p < .001; STAI state p = .015 and STAI trait p < .001at 6 months of life) after the intervention in the TG compared to the CG. Pediatric follow-up at 6 months demonstrated significant differences between groups in babies' development assessment (manipulation p = .003; language p < .001; sociability p < .001). The GIO helped to ensure healthy development of the baby and reduction of the mothers' depressive-anxiety symptomatology.

Maternal antenatal mood and child development: an exploratory study of treatment effects on child outcomes up to 5 years.

Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children's development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.

Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study.

Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex-specific mechanisms that underpin fetal programming.

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3.

BACKGROUND: Maternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression. METHOD: A diagnosis of depression during pregnancy was recorded from Manchester cohort participants' medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression. RESULTS: In a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively). CONCLUSIONS: This study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

A Role for the Placenta in Programming Maternal Mood and Childhood Behavioural Disorders.

Substantial data demonstrate that the early-life environment, including in utero, plays a key role in later life disease. In particular, maternal stress during pregnancy has been linked to adverse behavioural and emotional outcomes in children. Data from human cohort studies and experimental animal models suggest that modulation of the developing epigenome in the foetus by maternal stress may contribute to the foetal programming of disease. Here, we summarise insights gained from recent studies that may advance our understanding of the role of the placenta in mediating the association between maternal mood disorders and offspring outcomes. First, the placenta provides a record of exposures during pregnancy, as indicated by changes in the placental trancriptome and epigenome. Second, prenatal maternal mood may alter placental function to adversely impact foetal and child development. Finally, we discuss the less well established but interesting possibility that altered placental function, more specifically changes in placental hormones, may adversely affect maternal mood and later maternal behaviour, which can also have consequence for offspring well-being.

Salivary alpha-amylase stability, diurnal profile and lack of response to the cold hand test in young women.

Salivary cortisol measurement has proved useful for the non-invasive study of the hypothalamic-pituitary-adrenocortical axis, and salivary alpha-amylase has been suggested as a comparable marker for the sympathetic system. Despite some studies showing an increase in salivary alpha-amylase after challenges that stimulate the sympathetic nervous system, questions remain about interpretation. The aims of this study were to explore the stability of salivary alpha-amylase, its diurnal profile, response to the cold hand test, and correlation with cortisol. Salivary alpha-amylase was stable following 5 days at room temperature, and five freeze-thaw cycles. Its diurnal profile was opposite to that of cortisol. There was no salivary alpha-amylase response to the cold hand stress test, in the morning (11am) or afternoon (3pm), unlike cortisol which showed a response in the afternoon in the same samples. There was no correlation between salivary alpha-amylase and cortisol at any time. In conclusion, salivary alpha-amylase is stable to a range of conditions. Its diurnal pattern is compatible with sympathetic stimulation. Lack of response to the cold hand test suggests that secretion of salivary alpha-amylase is controlled by mechanisms more complex than sympathetic regulation alone.

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-betaHSD2, 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.

Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness.

BACKGROUND: Animal studies have shown that prenatal stress has persisting effects on several aspects of offspring development; more recent studies show that this effect may be eliminated by positive postnatal rearing. Human studies of prenatal anxiety/stress are now also beginning to document links between antenatal stress/anxiety and behavioural and cognitive development of the child; however, there is no human evidence as to whether the early caregiving environment moderates the effect of antenatal anxiety/stress on child outcomes. METHODS: Antenatal and postnatal measures of stress were collected on 123 women who were recruited from an antenatal clinic. Laboratory-based assessment of the children's cognitive development and fearfulness were assessed when the children were aged 17 months. In addition, child-parent attachment quality was assessed using the Strange Situation. RESULTS: Attachment classification moderated the link between antenatal stress and observed fearfulness. The effect of antenatal stress on fearfulness was most accentuated in children with an Insecure/Resistant attachment classification; the significant antenatal stress x attachment classification interaction held after controlling for postnatal stress and obstetric, social and demographic factors. Attachment did not moderate the effects of antenatal anxiety on cognitive development. DISCUSSION: These findings provide the first human evidence that postnatal parenting may moderate the adverse effects of antenatal stress. These results raise developmental questions about the timing and effect of interventions to reduce the adverse effects of antenatal stress exposure.

Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming.

Both animal and human studies have shown that maternal stress or anxiety during pregnancy is associated with increased risk of disturbance in offspring neurodevelopment and behaviour. In animal models, increased foetal exposure to glucocorticoids has been found to be one mechanism for such foetal programming. Little is understood of the mediating mechanisms in humans, and one aim of our research programme is to investigate this further. This review presents a synopsis of some of our recent results. We aimed to test the hypothesis that maternal anxiety was associated with raised maternal cortisol, and that this in turn was related to increased foetal exposure to cortisol. We studied this by recruiting women at amniocentesis, obtained their Spielberger State Anxiety scores, and assessed maternal plasma cortisol and amniotic fluid cortisol. We also examined maternal plasma and amniotic fluid testosterone levels. Awaiting amniocentesis was in general anxiogenic, but with a wide range of anxiety scores. Maternal anxiety was significantly associated with plasma cortisol before 17 weeks, albeit of modest magnitude (r = 0.0.23), and not after 17 weeks of gestation. This is probably due to the known attenuation of the maternal hypothalamic-pituitary-adrenal axis with increasing gestation. We found a strong correlation between maternal plasma and amniotic fluid cortisol levels, which increased with gestation and became robust after 18 weeks. This correlation increased with maternal anxiety, suggesting a possible effect of maternal mood on placental function. There was a positive correlation between cortisol and testosterone in amniotic fluid, in both male and female foetuses independent of maternal anxiety, plasma testosterone, gestational age, and time of collection. Foetal stress may be associated with increased foetal exposure to testosterone. However, maternal anxiety did not predict amniotic fluid cortisol or testosterone level. Thus, the role of these hormones in mediating the effect of maternal mood on foetal development in humans remains to be demonstrated.

Postnatal depression and mother and infant outcomes after infant massage.

BACKGROUND: Postnatal depression can be a long lasting condition which affects both the mother and her baby. A pilot study indicated that attending baby massage improved maternal depression and mother-infant interactions. The current study further investigates any benefits of baby massage for mothers with postnatal depression and their infants. METHODS: Mothers scoring (3)13 on the Edinburgh Postnatal Depression Scale (EPDS) at 4 weeks postpartum were randomly assigned to attend baby massage classes (n=31) or a support group (n=31). They completed depression, anxiety and Infant Characteristics Questionnaires and were filmed interacting with their infants before and after 6 intervention sessions, and at one year. Thirty four non-depressed mothers also completed the study. RESULTS: More of the massage than support group mothers showed a clinical reduction in EPDS scores between four weeks and outcome (p<0.05). At one year, massage-group mothers had non-depressed levels of sensitivity of interaction with their babies, whereas the support group did not. There were no other differences in either mother or child between the two intervention groups. Depressed mothers did not achieve control depression or anxiety scores at one year. LIMITATIONS: For ethical reasons, the study did not include a control group of depressed mothers who did not receive an intervention. CONCLUSIONS: Both intervention groups showed reductions in depression scores across the study period, but the massage group did better on some indices. They also had somewhat better interactions with their infants at one year, but these effects were limited.

Endogenous oxidized indoles share inhibitory potency against [3H]isatin binding in rat brain.

Isatin is an endogenous oxidized indole that influences a range of processes in vivo and in vitro. It has a distinct and discontinuous distribution in the brain and [3H]isatin binding sites are widely distributed in rat brain sections. The highest labelling is found in hypothalamic nuclei and in the cortex, hippocampus, and cerebellum (Crumeyrolle-Arias et al., 2003). However, the properties of most isatin binding sites and their physiological ligands remain unknown. In the present study the effects of three endogenous oxidized indoles (oxindole, 5-hyxdoxyoxindole, and isatin) on [3H]isatin binding were investigated in rat brain sections. In most regions cold isatin (0.2 mM) significantly reduced [3H]isatin binding. In addition to isatin, the other endogenous oxidized indoles, 5-hydroxyoxindole and oxindole were effective in displacing [3H]isatin. Total irreversible inhibition of monoamine oxidases caused inhibition of specific [3H]isatin binding in 7 of 10 brain region studied. This was accompanied by altered sensitivity of [3H]isatin binding to these indoles, including regions where a decrease of specific binding was not detected. The combinations of the three oxidized indoles produced two clear effects: augmentation (potentiation) and attenuation (blockade) of inhibitory activity compared with the independent effects of these compounds. The different effects of oxidized indoles and their combinations (isatin + 5-hydroxyoxindole and isatin + oxindole) in various brain regions therefore suggest an interaction of [(3H]isatin with different and multiple isatin-binding sites, which exhibit different sensitivity to endogenous oxidizing indoles.

[Criteria for evaluation of functional importance of endogenous analogues of pharmacological regulators].

Some criteria for the evaluation of the functional importance of endogenous analogues of pharmacological drugs are proposed. For endogenous regulators, these include opposite changes in their content in opposite (patho)physiological states, accompanied by corresponding changes in the functional activity of enzymes sensitive to changes in their level; regulation of target enzymes by physiological concentrations of such endogenous compounds. The applicability of these criteria has been demonstrated using tribulin, the endogenous family of inhibitors of monoamine oxidases.

Amniotic fluid testosterone: relationship with cortisol and gestational age.

INTRODUCTION: Foetal exposure to testosterone is increasingly implicated in the programming of future reproductive and non-reproductive behaviour. Some outcomes associated with prenatal exposure to testosterone may be predicted from exposure to prenatal stress, suggesting a link between them. The peak serum levels of testosterone in the foetus are thought to be around 14-18 weeks' gestation, and we explored testosterone levels at different gestations. Although best investigated in foetal plasma, this is now difficult because of the decline in frequency of foetal blood sampling; in this study, we used amniotic fluid as a biomarker to investigate foetal exposure. AIMS: To investigate the relationship between amniotic fluid testosterone, amniotic fluid cortisol, foetal gender, and gestational age. METHODS: Paired amniotic fluid and maternal plasma samples were collected from 264 pregnant women undergoing amniocentesis between 15 and 37 weeks' gestation (median 17 weeks [119 days]). Total testosterone and cortisol in amniotic fluid, and total plasma testosterone (maternal) were measured by radioimmunoassay. RESULTS: Amniotic fluid testosterone levels were higher in male than in female foetuses, with a median (interquartile range) of 0.85 nmol/l (0.60-1.17 nmol/l) and 0.28 nmol/l (0.175-0.45 nmol/l), respectively. No relationship between amniotic fluid testosterone and gestational age was detected in either sex. Amniotic fluid testosterone correlated positively with amniotic fluid cortisol in both sexes (r = 0.30 male foetuses, r = 0.33 female foetuses, P < 0.001 for both), and remained significant in multivariate analysis. CONCLUSION: Testosterone in amniotic fluid did not change with gestation in the second and third trimester, raising questions about the timing of the reported early peak in the male foetus. The positive correlation between cortisol and testosterone in amniotic fluid suggests that increased foetal exposure to cortisol may also be associated with increased exposure to testosterone.

Ontogeny of foetal exposure to maternal cortisol using midtrimester amniotic fluid as a biomarker.

OBJECTIVE: There is increasing evidence that antenatal stress has long-lasting effects on child development, but there is less accord on the mechanisms and the gestational window of susceptibility. One possible mechanism is by foetal exposure to maternal cortisol. To explore this, we investigated the relationship between cortisol in maternal plasma and amniotic fluid, and any moderating influence of gestational age. PATIENTS AND MEASUREMENTS: Two hundred and sixty-seven women awaiting amniocentesis for karyotyping were studied. Samples were collected between 0900 and 1730 h. Gestational age was determined to the nearest day by ultrasound biometry and time of collection noted to the nearest 15 min. Total cortisol was measured by radioimmunoassay in paired amniotic fluid and maternal blood samples (n = 267) [gestation range 15-37 weeks, median 17 weeks (119 days)]. RESULTS: Both maternal and amniotic fluid cortisol levels increased with gestation (r = 0.25, P < 0.001; r = 0.33 P < 0.001, respectively). Amniotic fluid cortisol was positively correlated with time of collection (r = 0.22, P < 0.001) and negatively with maternal age (r =-0.24, P < 0.001). There was a positive correlation between amniotic fluid cortisol with maternal plasma levels (r = 0.32, P < 0.001), which persisted after multivariate analysis controlling for gestation, time of collection and maternal age. The association appeared to be dependent on gestational age, being nonsignificant at 15-16 weeks' gestation and increasing in strength thereafter. CONCLUSION: This study shows a positive correlation between maternal and amniotic fluid cortisol levels, which becomes robust from 17 to 18 weeks onwards. The results provide support for the hypothesis that alterations in maternal cortisol may be reflected in amniotic fluid levels from this gestation.

[Interaction of pyruvate kinase with isatin and deprenyl].

The glycolytic enzyme, pyruvate kinase, exhibits moderate affinity [3H]isatin binding (KD approximately 10 microM), which is inhibited by ATP (IC50 25 microM) and deprenyl (IC50 5 microM). Interaction of pyruvate kinase with isatin and its inhibition by ATP and deprenyl has also been confirmed using an independent biosensor technique and immobilized isatin analogue, aminoisatin. This effect has some specificity because the enzyme, creatine phosphokinase, does not exhibit specific isatin-binding. It is suggested that interaction of pyruvate kinase with isatin may reflect some non-glycolytic functions of this enzyme.

Maternal anxiety at amniocentesis and plasma cortisol.

OBJECTIVES: To assess whether anticipation of amniocentesis is linked with maternal anxiety, and whether this anxiety is associated with increased maternal plasma cortisol. METHODS: Two hundred and fifty-four women awaiting a morning amniocentesis for karyotyping (gestation range 15-37 weeks, median 17 weeks) completed Spielberger state and trait anxiety inventory (STAI) questionnaires, and provided blood samples immediately before the procedure for cortisol assay. Six hundred and five women at mean gestation of 20 weeks, attending the same hospital for routine ultrasound but not for amniocentesis, also completed Spielberger STAI questionnaires and served as a comparison group for the anxiety ratings. RESULTS: Mean state and trait anxiety scores (+/- SD) in the comparison group of 605 women at mean gestation of 20 weeks were 36.1 +/- 10.2 (range 20-70) and 35.6 +/- 8.9 (range 20-73), respectively. The mean state anxiety score (+/-SD) of 49.8 +/- 14.0 (range 20-77) of the amniocentesis group was considerably higher than the comparison group (p < 0.001), although the mean trait anxiety score in the amniocentesis group was similar at 36.4 +/- 8.6 (range 21-60). The state, but not trait, anxiety correlated with plasma cortisol (r = 0.176, p = 0.005). Maternal cortisol in the amniocentesis group increased with gestational age (r = 0.310, p < 0.001), whereas state anxiety scores showed no significant change with increase in gestational age (r = - 0.042, ns). Multivariate analysis demonstrated that maternal state anxiety was positively correlated with plasma cortisol independent of gestation and time of collection. CONCLUSION: Women awaiting amniocentesis experience a high state anxiety associated with modestly increased plasma cortisol.

The HPA axis and perinatal depression: a hypothesis.

Episodes of depression and anxiety are as common during pregnancy as postpartum. Some start in pregnancy and resolve postpartum, others are triggered by parturition and some are maintained throughout. In order to determine any biological basis it is important to delineate these different subtypes. During pregnancy, as well as the rise in plasma oestrogen and progesterone there is a very large increase in plasma corticotropin releasing hormone (CRH), and an increase in cortisol. The latter reaches levels found in Cushing's syndrome and major melancholic depression. Levels of all these hormones drop rapidly on parturition.We here suggest that the symptoms of antenatal and postnatal depression may be different, and linked in part with differences in the function of the hypothalamic pituitary adrenal (HPA) axis. There are two subtypes of major depression, melancholic and atypical, with some differences in symptom profile, and these subtypes are associated with opposite changes in the HPA axis. Antenatal depression may be more melancholic and associated with the raised cortisol of pregnancy, whereas postnatal depression may be more atypical, triggered by cortisol withdrawal and associated with reduced cortisol levels. There is evidence that after delivery some women experience mild bipolar II depression, and others experience post traumatic stress disorder. Both of these are associated with atypical depression. It may also be that some women are genetically predisposed to depression of the melancholic type and some to depression of the atypical type. These women may be more or less vulnerable to depression at the different stages of the perinatal period.

Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl.

There is evidence that the binding of deprenyl, a monoamine oxidase (MAO) B inhibitor, and other propargylamines to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is primarily responsible for their neuroprotective and antiapoptotic effects. Thus, GAPDH may be a target for other neuroprotective drugs. Using two independent approaches, radioligand analysis and an optical biosensor technique, we demonstrate here that GAPDH also interacts with the endogenous, reversible MAO B inhibitor, isatin. Deprenyl inhibited both [3H]isatin binding to GAPDH, and the binding of this enzyme to an isatin analogue, 5-aminoisatin, immobilized on to an optical biosensor cell. Another MAO inhibitor, tranylcypromine, was ineffective. Both deprenyl and isatin inhibited GAPDH-mediated cleavage of E. coli tRNA, and their effects were not additive. We suggest that isatin may be an endogenous partial functional agonist of deprenyl in its effect on GAPDH and GAPDH-mediated RNA cleavage. Changes in level of endogenous isatin may influence the neuroprotective effect of deprenyl in vivo.