Short interpregnancy intervals and adverse perinatal outcomes in high-resource settings: An updated systematic review.

BACKGROUND: This systematic review summarises association between short interpregnancy intervals and adverse perinatal health outcomes in high-resource settings to inform recommendations for healthy birth spacing for the United States. METHODS: Five databases and a previous systematic review were searched for relevant articles published between 1966 and 1 May 2017. We included studies meeting the following criteria: (a) reporting of perinatal health outcomes after a short interpregnancy interval since last livebirth; (b) conducted within a high-resource setting; and (c) estimates were adjusted for maternal age and at least one socio-economic factor. RESULTS: Nine good-quality and 18 fair-quality studies were identified. Interpregnancy intervals <6 months were associated with a clinically and statistically significant increased risk of adverse outcomes in studies of preterm birth (eg, aOR ≥ 1.20 in 10 of 14 studies); spontaneous preterm birth (eg, aOR ≥ 1.20 in one of two studies); small-for-gestational age (eg, aOR ≥ 1.20 in 5 of 11 studies); and infant mortality (eg, aOR ≥ 1.20 in four of four studies), while four studies of perinatal death showed no association. Interpregnancy intervals of 6-11 and 12-17 months generally had smaller point estimates and confidence intervals that included the null. Most studies were population-based and few included adjustment for detailed measures of key confounders. CONCLUSIONS: In high-resource settings, there is some evidence showing interpregnancy intervals <6 months since last livebirth are associated with increased risks for preterm birth, small-for-gestational age and infant death; however, results were inconsistent. Additional research controlling for confounding would further inform recommendations for healthy birth spacing for the United States.

Short interpregnancy intervals and adverse maternal outcomes in high-resource settings: An updated systematic review.

BACKGROUND: Currently, no federal guidelines provide recommendations on healthy birth spacing for women in the United States. This systematic review summarises associations between short interpregnancy intervals and adverse maternal outcomes to inform the development of birth spacing recommendations for the United States. METHODS: PubMed/Medline, POPLINE, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, and a previous systematic review were searched to identify relevant articles published from 1 January 2006 and 1 May 2017. Included studies reported maternal health outcomes following a short versus longer interpregnancy interval, were conducted in high-resource settings, and adjusted estimates for at least maternal age. Two investigators independently assessed study quality and applicability using established methods. RESULTS: Seven cohort studies met inclusion criteria. There was limited but consistent evidence that short interpregnancy interval is associated with increased risk of precipitous labour and decreased risks of labour dystocia. There was some evidence that short interpregnancy interval is associated with increased risks of subsequent pre-pregnancy obesity and gestational diabetes, and decreased risk of preeclampsia. Among women with a previous caesarean delivery, short interpregnancy interval was associated with increased risk of uterine rupture in one study. No studies reported outcomes related to maternal depression, interpregnancy weight gain, maternal anaemia, or maternal mortality. CONCLUSIONS: In studies from high-resource settings, short interpregnancy intervals are associated with both increased and decreased risks of adverse maternal outcomes. However, most outcomes were evaluated in single studies, and the strength of evidence supporting associations is low.

The anatomical distance of functional connections predicts brain network topology in health and schizophrenia.

The human brain is a topologically complex network embedded in anatomical space. Here, we systematically explored relationships between functional connectivity, complex network topology, and anatomical (Euclidean) distance between connected brain regions, in the resting-state functional magnetic resonance imaging brain networks of 20 healthy volunteers and 19 patients with childhood-onset schizophrenia (COS). Normal between-subject differences in average distance of connected edges in brain graphs were strongly associated with variation in topological properties of functional networks. In addition, a club or subset of connector hubs was identified, in lateral temporal, parietal, dorsal prefrontal, and medial prefrontal/cingulate cortical regions. In COS, there was reduced strength of functional connectivity over short distances especially, and therefore, global mean connection distance of thresholded graphs was significantly greater than normal. As predicted from relationships between spatial and topological properties of normal networks, this disorder-related proportional increase in connection distance was associated with reduced clustering and modularity and increased global efficiency of COS networks. Between-group differences in connection distance were localized specifically to connector hubs of multimodal association cortex. In relation to the neurodevelopmental pathogenesis of schizophrenia, we argue that the data are consistent with the interpretation that spatial and topological disturbances of functional network organization could arise from excessive "pruning" of short-distance functional connections in schizophrenia.

Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence.

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

Side Effects and Health Benefits of Depot Medroxyprogesterone Acetate: A Systematic Review.

OBJECTIVE: Counseling about potential side effects and health benefits of contraceptive methods could facilitate continued method use and method satisfaction, yet no evidence-based compilation of side effects and benefits exists to aid such counseling. Among contraceptive methods in the United States, depot medroxyprogesterone acetate (DMPA) injectables have the highest discontinuation rates, and most discontinuation is attributable to side effects. This review examines the side effects and health benefits of DMPA to inform counseling. DATA SOURCES: We searched PubMed, POPLINE, EMBASE, Web of Science, Campbell Collaboration Library of Systematic Reviews, the Cochrane Database of Systematic Reviews, the Cochrane Center Register of Controlled Trials, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We included English-language studies published from 1985 to 2016 that enrolled healthy, nonbreastfeeding females aged 13-49 years at risk of unintended pregnancy, compared intramuscular or subcutaneous progestin-only injectables to a contemporaneous comparison group, and addressed at least one key question: 1) What side effects are associated with progestin-only injectable contraceptive use? 2) What health benefits are associated with progestin-only injectable contraceptive use? Study quality was assessed using criteria from the U.S. Preventive Services Task Force. TABULATION, INTEGRATION, AND RESULTS: Twenty-four studies met inclusion criteria. None were randomized controlled trials. There were 13 prospective cohort, five retrospective cohort, four case-control, and two cross-sectional studies. Studies of moderate or high risk of bias suggest an association between DMPA use and weight gain, increased body fat mass, irregular bleeding, and amenorrhea. Inconsistent evidence exists for an association between DMPA use and mood or libido changes. Limited evidence exists for an association between DMPA use and decreased risk of cancers and tubal infertility. CONCLUSION: Higher-quality research is needed to clarify DMPA's side effects and benefits. In absence of such evidence, patient-centered counseling should incorporate the available evidence while acknowledging its limitations and recognizing the value of women's lived experiences.

Lack of gender influence on cortical and subcortical gray matter development in childhood-onset schizophrenia.

BACKGROUND: Progressive cortical gray matter (GM) abnormalities are an established feature of schizophrenia and are more pronounced in rare, severe, and treatment refractory childhood-onset schizophrenia (COS) cases. The effect of sex on brain development in schizophrenia is poorly understood and studies to date have produced inconsistent results. METHODS: Using the largest to date longitudinal sample of COS cases (n = 104, scans = 249, Male/Female [M/F] = 57/47), we compared COS sex differences with sex differences in a sample of matched typically developing children (n = 104, scans = 244, M/F = 57/47), to determine whether or not sex had differential effects on cortical and subcortical brain development in COS. RESULTS: Our results showed no significant differential sex effects in COS for either GM cortical thickness or subcortical volume development (sex × diagnosis × age interaction; false discovery rate q = 0.05). CONCLUSION: Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children.

Psychotic symptoms and gray matter deficits in clinical pediatric populations.

BACKGROUND: Neuroanatomic studies have not yet addressed how subtle phenotypic distinctions in psychosis alter the underlying brain changes, and whether there is evidence for psychosis as a dimensional construct. We explored the relationship of cortical GM thickness to psychotic phenotypes in children. METHODS: Cross-sectional comparison of anatomic brain imaging between patients referred as childhood-onset schizophrenia (COS) but ruled out after a drug free inpatient observation. Groups included: patients with no evidence of psychosis (n=22) after drug free observation, patients with psychosis not otherwise specified (PNOS; total n=29) further divided into those without other axis I diagnoses (n=13) and those with other axis I comorbidities (n=16), age/sex matched COS patients (n=48), and 51 matched healthy controls. GM cortical thickness was compared between the groups, and regressed on patients' SAPS, SANS and GAS scores. RESULTS: Patients with no evidence of psychosis showed no cortical GM deficits. Presence of psychosis (PNOS with or without co-morbidities) showed some areas of temporal and prefrontal deficits, more subtle compared to the extensive bilateral cortical deficits seen for COS. GAS SAPS and SANS scores showed a relationship with cortical GM thickness although it did not survive adjustment for multiple comparisons. CONCLUSIONS: These results highlight the need for careful phenotypic characterization, as subtle diagnostic distinctions appear to reflect distinct underlying patterns of brain deficits. The incremental nature of cortical deficits from no psychosis to PNOS to COS may further support dimensional model for psychosis.

Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia.

CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

Normalization of cortical gray matter deficits in nonpsychotic siblings of patients with childhood-onset schizophrenia.

OBJECTIVE: Cortical gray matter (GM) abnormalities in patients with childhood-onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to "normalize" by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls. METHOD: Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval-matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. RESULTS: As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17. CONCLUSIONS: Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings.

Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients.

OBJECTIVE: Previous anatomic studies have established a reduction in hippocampal volume in schizophrenia, but few have investigated the progressive course of these changes and whether they are trait markers. In the present study, the authors examined hippocampal volumes in relation to age for patients with childhood-onset schizophrenia, their nonpsychotic healthy siblings, and healthy comparison subjects. METHOD: Anatomic brain magnetic resonance scans were obtained in childhood-onset schizophrenia probands (N=89, 198 scans), their nonpsychotic full siblings (N=78, 172 scans), and matched healthy comparison subjects (N=79, 198 scans) between the ages of 10 and 29 years. Total, left, and right hippocampal volumes were measured using FreeSurfer software and analyzed using a linear mixed-model regression covarying for sex and intracranial volume. RESULTS: Childhood-onset schizophrenia probands had a fixed reduction in hippocampal volumes (total, left, and right) relative to both nonpsychotic siblings and healthy comparison subjects, whereas there were no significant volumetric or trajectory differences between nonpsychotic siblings and healthy comparison subjects. CONCLUSIONS: Fixed hippocampal volume loss seen in childhood-onset schizophrenia, which is not shared by healthy siblings, appears to be related to the illness. Decreased hippocampal volume is not strongly genetically related but represents an important intermediate disease phenotype.

Effects of clozapine and olanzapine on cortical thickness in childhood-onset schizophrenia.

BACKGROUND: Little is known about the effects of antipsychotic medications on gray matter (GM) in schizophrenia. Although clozapine remains the most effective antipsychotic medication in treatment-refractory cases, it is unknown whether it has a differential effect on GM development. METHODS: In an exploratory analysis, we used automated cortical thickness measurements and prospectively scanned childhood-onset schizophrenia (COS) patients who were maintained on one medication. Two atypical antipsychotic medications, clozapine (n=12, 37 scans) and olanzapine (n=12, 33 scans) were compared with respect to effects on cortical development, in contrast to GM trajectories of matched controls. RESULTS: There were no significant differences in the trajectories of cortical thickness between the two treatment groups with the exception of a small circumscribed area in the right prefrontal cortex, where the olanzapine group showed thicker cortex. As expected, both groups showed thinner GM compared to matched controls. CONCLUSIONS: Although these analyses do not rule out effects of antipsychotic medications on GM development in schizophrenia, they show no differential effect between clozapine and olanzapine on GM trajectory.