Clinical trials in the pandemic age: What is fit for purpose?

It is critical to ensure that COVID-19 studies provide clear and timely answers to the scientific questions that will guide us to scalable solutions for all global regions. Significant challenges in operationalizing trials include public policies for managing the pandemic, public health and clinical capacity, travel and migration, and availability of tests and infrastructure. These factors lead to spikes and troughs in patient count by location, disrupting the ability to predict when or if a trial will reach recruitment goals. The focus must also be on understanding how to provide equitable access to these interventions ensuring that interventions reach those who need them the most, be it patients in low resource settings or vulnerable groups.  We introduce a website to be used by The Bill & Melinda Gates Foundation, Wellcome Trust, and other funders of the COVID Therapeutics Accelerator that accept proposals for future clinical research. The portal enables evaluations of clinical study applications that focus on study qualities most likely to lead to informative outcomes and completed studies.

Female infants are more susceptible to the effects of maternal antenatal depression; findings from the Pelotas (Brazil) Birth Cohort Study.

BACKGROUND: We utilised data from the 2015 Pelotas Birth Cohort, a large prospective cohort in southern Brazil, to examine the association of moderate and severe antenatal depression with child birth outcomes and explore interactions with sociodemographic characteristics. METHODS: Data was available for n = 3046 participants and their infants. We measured antenatal depression using the Edinburgh Postnatal Depression Scale (EPDS, ≥13 for moderate and ≥17 for severe depression). Outcome measures included gestational age, birth weight, length and head circumference, using the Intergrowth-21st standards. We controlled for known confounders including obstetric risk. RESULTS: We did not find differences in childbirth outcomes by maternal depression status for participants with at least moderate depression, although there was an increased risk for female offspring to be small for gestational age (SGA, OR 2.33[1.37,3.97]). For severe depression (EPDS≥17) we found an increased risk for lower APGAR scores (OR 1.63[1.02,2.60]) and being SGA (OR 1.77[1.06,2.97], with an increased risk for female offspring in particular to be in lower weight centiles (-10.71 [-16.83,-4.60]), to be SGA (OR 3.74[1.89, 7.44]) and in the lower 10th centile for length (OR 2.19[1.25,3.84]). LIMITATIONS: include the use of a maternal report questionnaire to ascertain depressive symptoms. CONCLUSIONS: In this recent large longitudinal cohort in Brazil we did not find independent effects of depression on adverse birth outcomes or interactions with sociodemographic characteristics. We found an increased risk of being SGA for female offspring of women with moderate and severe depression, in line with other research suggesting females may be more susceptible to antenatal disturbances. FUNDING: This work was supported by the Wellcome Trust, United Kingdom (095582), the Brazilian National Research Council (CNPq) and the Coordination for the Improvement of Higher Education Personnel (CAPES). EN was supported by the UK Economic and Social Research Council GCRF Postdoctoral Fellowship (ES/P009794/1).

Association of Persistent and Severe Postnatal Depression With Child Outcomes.

Importance: Maternal postnatal depression (PND) is common and associated with adverse child outcomes. These effects are not inevitable, and it is critical to identify those most at risk. Previous work suggests that the risks of adverse outcomes are increased when PND is severe and persistent, but this has not been systematically studied. Objective: To examine the association between differing levels of persistence and severity of PND and long-term child outcomes. Design, Setting, and Participants: The sample for this observational study comprised participants in the Avon Longitudinal Study of Parents and Children in the United Kingdom. Three thresholds of PND severity-moderate, marked, and severe-were defined using the self-rated Edinburgh Postnatal Depression Scale (EPDS). Depression was defined as persistent when the EPDS score was above the threshold level at both 2 and 8 months after childbirth. For each of these severity and persistence categories, the following were examined: (1) the trajectories of later EPDS scores (6 time points between 21 months and 11 years after childbirth) and (2) child outcomes-behavioral problems at 3.5 years of age, school-leaving mathematics grades at 16 years of age, and depression at 18 years of age. Data analysis was conducted from July 12, 2016, to February 8, 2017. Main Outcomes and Measures: Child behavioral problems at 3.5 years of age using the Rutter total problems scale, school-leaving mathematics grades at 16 years of age extracted from records of external national public examinations, and offspring depression at 18 years of age using the Clinical Interview Schedule-Revised. Results: For the 9848 mothers in the sample, the mean (SD) age at delivery was 28.5 (4.7) years. Of the 8287 children, 4227 (51%) were boys and 4060 (49%) were girls. Compared with women with PND that was not persistent and women who did not score above the EPDS threshold, for all 3 severity levels, women with persistent PND showed elevated depressive symptoms up to 11 years after childbirth. Whether persistent or not, PND doubled the risk of child behavior disturbance. The odds ratio (OR) for child behavioral disturbance for mothers with moderate PND was 2.22 (95% CI, 1.74-2.83), for mothers with marked PND was 1.91 (95% CI, 1.36-2.68), and for mothers with severe PND was 2.39 (95% CI, 1.78-3.22). Persistence of severe PND was particularly important to child development, substantially increasing the risk for behavioral problems at 3.5 years of age (OR, 4.84; 95% CI, 2.94-7.98), lower mathematics grades at 16 years of age (OR, 2.65; 95% CI, 1.26-5.57), and higher prevalence of depression at 18 years of age (OR, 7.44; 95% CI, 2.89-19.11). Conclusions and Relevance: Persistent and severe PND substantially raises the risk for adverse outcome on all child measures. Meeting criteria for depression both early and late in the postnatal year, especially when the mood disturbance is severe, should alert health care professionals to a depression that is likely to be persistent and to be associated with an especially elevated risk of multiple adverse child outcomes. Treatment for this group should be prioritized.

Mitigating the effect of persistent postnatal depression on child outcomes through an intervention to treat depression and improve parenting: a randomised controlled trial.

BACKGROUND: Maternal postnatal depression occurs following 10-15% of births and is associated with a range of negative child outcomes. Risks to children are particularly increased when postnatal depression is persistent. We aimed to examine whether a parenting video-feedback therapy (VFT) intervention versus a control treatment of progressive muscle relaxation (PMR), both added to cognitive behavioural therapy (CBT) for persistent postnatal depression, would lead to improved child outcomes at age 2 years. METHODS: In this two-arm, parallel-design, individually randomised controlled trial, we recruited a community sample of women aged 18 years or older living within 50 miles of Oxford, UK, between 4·5 and 9·0 months post partum. All participants met diagnostic criteria for current major depressive disorder that had persisted for at least 3 months and had infants at 35 or more weeks of gestation, with a birthweight of 2000 g or greater, and without serious neonatal complications. Through a centralised service, women were randomly assigned by use of a minimisation algorithm, to receive either VFT or PMR, balanced for child sex, temperament, age, socioeconomic status, and severity of depression. Both groups also received CBT for depression. Primary outcomes were child cognitive development, language development, behaviour problems, and attachment security at age 2 years. There were 11 home-based treatment sessions before child age 1 year, followed by two booster sessions in the second year. Assessors were masked to treatment group allocation. All analyses were done according to the intention-to-treat principle. This trial is registered with the ISRCTN registry, number ISRCTN07336477. FINDINGS: Between March 18, 2011, and Dec 9, 2013, we randomly assigned 144 women, 72 to each group. Primary outcome data were available for 62-64 (86-89%) VFT and 67-68 (93-94%) PMR participants. There were no group differences in child outcome (cognitive development, adjusted difference -1·01 [95% CI -5·11 to 3·09], p=0·63; language development, 1·33 [-4·16 to 6·82], p=0·63; behaviour problems, -1·77 [-4·39 to 0·85], p=0·19; attachment security, 0·02 [-0·06 to 0·10], p=0·58), with both groups achieving scores similar to non-clinical norms on all outcomes. There were six serious adverse events: five in the VFT group (in two participants) and one in the PMR group. None was treatment-related. INTERPRETATION: The effect of persistent postnatal depression on children is a major public health issue. For both treatment groups there was sustained remission from depression, and child development outcomes were in the normal range. The precise mechanisms accounting for the observed positive child outcomes cannot be ascertained from this study. FUNDING: Wellcome Trust.

A different rhythm of life: sleep patterns in the first 4 years of life and associated sociodemographic characteristics in a large Brazilian birth cohort.

OBJECTIVE: Sleep is an important marker of healthy development and has been associated with emotional, behavioral, and cognitive development. There is limited longitudinal data on children's sleep with only a few reports from low- and middle-income countries (LMICs). We investigate sleep parameters and associated sociodemographic characteristics in a population-based longitudinal study in Pelotas, Brazil. METHODS: Data from the Pelotas 2004 Birth Cohort were used (N = 3842). Infant sleep was collected through maternal report at 3, 12, 24, and 48 months: sleep duration, bed and wake time, nighttime awakenings, co-sleeping and sleep disturbances (24 and 48 months). RESULTS: Compared to children in high-income countries (HICs), children in Brazil showed a substantial shift in rhythms with later bed and wake times by approximately 2 hours. These remain stable throughout the first 4 years of life. This population also shows high levels of co-sleeping which remain stable throughout (49.0-52.2%). Later bedtime was associated with higher maternal education and family income. Higher rates of co-sleeping were seen in families with lower income and maternal education and for children who were breastfed. All other sleep parameters were broadly similar to data previously reported from HICs. CONCLUSION: The shift in biological rhythms in this representative community sample of children in Brazil challenges our understanding of optimal sleep routine and recommendations.

Parenting and HIV.

With the widespread use of antiretroviral therapy and successful prevention of mother-to-child transmission the development of HIV-negative children with HIV-positive parents has become an important focus. There is considerable evidence that children's developmental risk is heightened because a parental HIV-diagnosis is associated with a range of potential problems such as depression, stigma and financial difficulties. Up to a third of children in sub-Saharan Africa (SSA) are cared for by an HIV-positive parent or caregiver. We review the mechanisms by which HIV affects parenting including its negative effects on parental responsiveness in the early years of parenting and parental avoidant coping styles and parenting deficits in the later years. We describe low-cost parenting interventions suited for low resourced HIV endemic settings.

Psychometric properties of the Generalized Anxiety Disorder Questionnaire - IV (GAD-Q-IV) in postpartum mothers.

Generalized anxiety disorder (GAD) is a mental disorder of which the main feature is persistent and impairing worry. GAD symptoms are common for women during the postpartum period and GAD prevalence rates have been reported as higher in postpartum mothers than in the general population. Currently, little psychometric evidence exists for a screening measure to detect the possible presence of diagnosable GAD for postpartum women. The purpose of this investigation was to gather psychometric information for the Generalized Anxiety Disorder Questionnaire-IV (GAD-Q-IV; Newman et al., 2002) with a sample of postpartum mothers. Factor analyses were conducted to determine the factor structure of the GAD-Q-IV in postpartum women. Receiver-operating characteristic (ROC) analysis was used to determine a range of potential GAD-Q-IV cut-off scores for detecting the likely presence of GAD in postpartum women. Results from this study provided evidence to justify a 1-factor structure for the GAD-Q-IV responses from postpartum women, which demonstrated structural, metric, and scalar invariance over time. Findings from these analyses provided evidence of incremental validity, as there was a significant increase in predicting GAD diagnoses when GAD-Q-IV responses were used compared with another measure of postpartum depression. Last, using ROC analysis, a range of GAD-Q-IV cut-off scores was determined, which can be applied to screening for the likely presence or absence of GAD in postpartum women. The evidence presented in this study suggests that the GAD-Q-IV could be a viable screening measure used to identify the likely presence of GAD in postpartum women so that further evaluations and treatments can be recommended. (PsycINFO Database Record

Antenatal depressive symptoms among pregnant women: Evidence from a Southern Brazilian population-based cohort study.

BACKGROUND: Antenatal depression (AD) is a major public health issue but evidence regarding its prevalence and associated factors in low and middle-income countries (LMICs) is limited. The aim of the study was to estimate the prevalence and identify risk factors for AD among Brazilian pregnant women. METHODS: All women living in the urban area of the city of Pelotas, Southern Brazil, with confirmed pregnancy and estimated delivery date in the year 2015, were invited to take part. Eligible pregnant women were recruited from health services. Symptoms of antenatal depression were assessed using the Edinburgh Postnatal Depression Scale (EPDS) by face-to-face interviews. A cutoff-point of 13 or more was used to define probable AD. RESULTS: EPDS scores were available for 4130 women. The prevalence of AD was 16% (95%CI 14·9-17·1). After adjustment for potential confounders, the factors most strongly associated with higher EPDS scores were a previous history of depression (PR 2·81; 95%CI 2·44-3·25), high parity (PR 1·72; 95%CI 1·38-2·15 - ≥2 children vs. 1 child) and maternal education (PR 5·47; 95%CI 4·22-7·09 - 0-4 vs. ≥12 years of formal education). LIMITATIONS: EPDS was administered through face-to-face interviews rather than questionnaires and some women may have felt uncomfortable reporting their symptoms leading to underreporting and consequently underestimation of the prevalence found. CONCLUSION: AD prevalence is substantially higher in Brazil than in high-income countries (HICs) but similar to other LMICs. Our study identified relevant risk factors that may be potential targets to plan interventions, particularly a history of depression.

Maternal postnatal depression and anxiety and their association with child emotional negativity and behavior problems at two years.

Postnatal maternal depression is associated with poorer child emotional and behavioral functioning, but it is unclear whether this occurs following brief episodes or only with persistent depression. Little research has examined the relation between postnatal anxiety and child outcomes. The present study examined the role of postnatal major depressive disorder (MDD) and generalized anxiety disorder (GAD) symptom chronicity on children's emotional and behavioral functioning at 24 months. Following postnatal screening mothers (n = 296) were identified as having MDD, GAD, MDD and GAD, or no disorder at 3 months postnatal; the average age was 32.3 (SD = 5.0), 91.9% self-identified as Caucasian, and 62.2% were married. Maternal disorder symptom severity was assessed by questionnaires and structured interview at 3, 6, 10, 14, and 24 months postpartum. At 24 months, child emotional negativity and behavior were assessed using questionnaires and by direct observation. Latent trait-state-occasion modeling was used to represent maternal disorder symptom chronicity; both stable trait and time-specific occasion portions of maternal symptomatology were examined in relation to child outcomes. Only the stable trait portion of maternal MDD and GAD symptom severity were related to maternal report of child behavior problems and higher levels of emotional negativity. Persistent maternal MDD, but not GAD, symptom severity was related to higher levels of child emotional negativity as measured observationally. These data suggest that children's behavior problems and emotional negativity are adversely affected by persistent maternal depression, and possibly anxiety. This has implications for interventions to prevent negative effects of postnatal psychopathology on children. (PsycINFO Database Record

Infant outcomes following treatment of antenatal depression: Findings from a pilot randomized controlled trial.

INTRODUCTION: Maternal antenatal depression is associated with an increased risk of emotional and behavioural problems in children. More recently antenatal depression has been associated with shorter sleep duration, higher number of awakenings and sleep problems in infants. Examining the effect of treatment of depression on child development is the next step in unravelling the complex association between antenatal depression and offspring development. METHODS: We used data from a pilot RCT of women with antenatal depression who received either Cognitive Behavioural Therapy (CBT) or Treatment as Usual (TAU), to examine infant sleep duration and temperament two months postpartum. Data was available for n=14 in the CBT group and n=11 in the TAU group. RESULTS: No differences by treatment arm were evident. Improvement in depression scores during pregnancy was associated with easier temperament (ß=-.45, p=.024) and shorter nocturnal sleep duration (ß=-.58, p=.003). The findings were more pronounced in the CBT group compared to the TAU group. LIMITATIONS: This was a pilot RCT and as such the sample size was small and there was some loss to follow up between the baseline and postnatal assessment. CONCLUSION: Improvement in antenatal depressive symptoms may have beneficial effects for the infant; whether these are directly through effects on foetal development or indirectly through changes in the postnatal mother-infant relationship remains to be determined.

Does Infant Reactivity Moderate the Association Between Antenatal Maternal Depression and Infant Sleep?

OBJECTIVE: A number of studies have established an association between antenatal maternal depression and infant sleep. One key question is whether all infants are equally susceptible to environmental influences, including the intrauterine environment. Reactive temperament has been examined as a plasticity factor, with accumulating evidence suggesting that infants with reactive temperament may be more susceptible to both positive and negative environmental influences. This study examines whether infant reactivity moderates any association between antenatal depression and infant sleep in 2 longitudinal studies: the Avon Longitudinal Study of Parents and Children (ALSPAC) and Generation R cohorts. METHODS: Maternal depression scores were assessed during pregnancy using Edinburgh Postnatal Depression Scale and Brief Symptom Inventory. Infant sleep duration and awakenings, in ALSPAC (N = 8318) and Generation R (N = 2241), were assessed at 18 and 24 months of age, respectively. Infant reactivity was assessed by temperament questionnaire at 6 months of age. RESULTS: Hierarchical linear regression models indicated a 3-way interaction between reactivity and gender moderating the effect of antenatal depression on infant sleep, on sleep duration in Generation R at 24 months (ß = .085, p < .001) in the whole sample and when limited to the Dutch/European group (ß = .055, p = .030), and on night awakenings at 18 months in ALSPAC (ß = -.085, p = .013). Boys with more reactive temperament exhibited shorter sleep duration and a higher number of awakenings when previously exposed to maternal symptoms of antenatal depression. CONCLUSION: For the first time, these findings highlight, in 2 large cohorts, that children with temperamental reactivity may be more vulnerable to antenatal depression, raising the possibility of targeted interventions to improve infant outcomes.

Paternal Depression in the Postnatal Period and Early Father-Infant Interactions.

Objective. Paternal depressive disorder is associated with adverse effects on child development. One possible mechanism for this is through the effects of the disorder on parenting capacities. The link between paternal depression and father-infant interactions was investigated at three-months postpartum. Design. Major depressive disorder was assessed in N = 192 fathers using a structured clinical interview (SCID). Altogether, 54 fathers met criteria for depression, and 99 fathers were categorized as non-depressed. Observational assessments of face-to-face father-infant interactions were conducted in an infant-seat setting and a floor-mat setting. Associations between paternal depression and father-infant interactions were analyzed. Results. Paternal depression is associated with more withdrawn parental behavior in interactions on the floor-mat. There were few other differences in observed interaction between depressed and non-depressed fathers. Conclusions. Fathers with depression may be more withdrawn, displaying less verbal and behavioral stimulation during interactions with their young infants. They may initiate a pattern of parenting that remains compromised, potentially affecting their children's development.

No moderating effect of 5-HTTLPR on associations between antenatal anxiety and infant behavior.

OBJECTIVE: Maternal antenatal anxiety is associated with an increased risk of behavioral disturbances in offspring. Recent work has suggested that the effect of maternal antenatal anxiety on infant temperament at 6 months is moderated by the serotonin transporter polymorphism 5-HTTLPR, with carriers of the short allele more susceptible to the adverse behavioral outcomes of maternal antenatal anxiety. These findings, however, are yet to be replicated and extended beyond infancy. The aim of the current study was to assess this same potential moderator (5-HTTLPR) in a large population-based cohort study, and to determine whether or not the effects persist into childhood and early adolescence. METHOD: Data from the Avon Longitudinal Study of Children and Parents (ALSPAC) cohort (N = 3,946) were used to assess whether the 5-HTTLPR genotype moderated the association between self-reported maternal antenatal anxiety (Crown Crisp Index) in pregnancy, and child temperament at 6 months (Infant Temperament Questionnaire), and also later behavioral and emotional problems on the Strengths and Difficulties Questionnaire from age 4 to 13 years. RESULTS: We found no evidence to suggest that the 5-HTTLPR polymorphism moderated the effects of maternal antenatal anxiety on infant temperament at 6 months or infant behavioral and emotional problems from childhood through to adolescence. CONCLUSION: Our results, based on a large prospective community sample that assessed children from infancy to early adolescence, provide a thorough test of, but no evidence for, a genetic moderation of the effects of maternal antenatal anxiety by 5-HTTLPR.

Paternal depression: an examination of its links with father, child and family functioning in the postnatal period.

BACKGROUND: Maternal depression is common and is known to affect both maternal and child health. One of the mechanisms by which maternal depression exerts its effects on child health is through an increased rate of parental disharmony. Fathers also experience depression, but the impact of this on family functioning has been less studied. The aim of this study was to investigate the association between paternal depressive disorder and family and child functioning, in the first 3 months of a child's life. METHODS: A controlled study comparing individual and familial outcomes in fathers with (n = 54) and without diagnosed depressive disorder (n = 99). Parental couple functioning and child temperament were assessed by both paternal and maternal report. RESULTS: Depression in fathers is associated with an increased risk of disharmony in partner relationships, reported by both fathers and their partners, controlling for maternal depression. Few differences in infant's reported temperament were found in the early postnatal period. CONCLUSIONS: These findings emphasize the importance of considering the potential for men, as well as women, to experience depression in the postnatal period. Paternal symptoms hold the potential to impact upon fathers, their partners, and their children.

Depression in fathers in the postnatal period: assessment of the Edinburgh Postnatal Depression Scale as a screening measure.

BACKGROUND: Postnatal depression commonly affects women after the birth of a child, and is associated with an increased risk of adverse outcomes for their children. A wide variety of measures have been used to screen for depression in the postnatal period but little research has investigated such measures with men. However depression can also affect men at this time, and this is associated with an independently increased risk of adverse child outcomes. The present study aimed to determine whether a reliable cut off point for the Edinburgh Postnatal Depression Scale (EPDS) can be established to screen fathers. METHOD: A sample of fathers was sent the EPDS at 7 weeks after the birth of their child. A structured clinical interview was conducted with 192 men to determine whether they were suffering from depression. RESULTS: Fathers with depression scored significantly higher on the EPDS than non-depressed fathers. A score of greater than 10 was found to be the optimal cut off point for screening for depression, with a sensitivity of 89.5% and a specificity of 78.2%. LIMITATIONS: The relatively modest participation rate means the results may not be fully generalisable to the whole population. CONCLUSION: The EPDS is shown to have reasonable sensitivity and specificity at a cut off score of over 10. The study shows that it is possible to screen fathers for depression in the postnatal period and it may be valuable to administer this measure to new fathers.