Timing of neonatal mortality and severe morbidity during the postnatal period: a systematic review

Objective: the objective of this review was to determine the timing of overall and cause-specific neonatal mortality and severe morbidity during the postnatal period (1-28 days).Introduction: despite significant focus on improving neonatal outcomes, many newborns continue to die or experience adverse health outcomes. While evidence on neonatal mortality and severe morbidity rates and causes are regularly updated, less is known on the specific timing of when they occur in the neonatal period.Inclusion criteria: this review considered studies that reported on neonatal mortality daily in the first week; weekly in the first month; or day 1, days 2-7, and days 8-28. It also considered studies that reported on timing of severe neonatal morbidity. Studies that reported solely on preterm or high-risk infants were excluded, as these infants require specialized care. Due to the available evidence, mixed samples were included (eg, both preterm and full-term infants), reflecting a neonatal population that may include both low-risk and high-risk infants.Methods: MEDLINE, Embase, Web of Science, and CINAHL were searched for published studies on December 20, 2019, and updated on May 10, 2021. Critical appraisal was undertaken by 2 independent reviewers using standardized critical appraisal instruments from JBI. Quantitative data were extracted from included studies independently by 2 reviewers using a study-specific data extraction form. All conflicts were resolved through consensus or discussion with a third reviewer. Where possible, quantitative data were pooled in statistical meta-analysis. Where statistical pooling was not possible, findings were reported narratively.Results: a total of 51 studies from 36 articles reported on relevant outcomes. Of the 48 studies that reported on timing of mortality, there were 6,760,731 live births and 47,551 neonatal deaths with timing known. Of the 34 studies that reported daily deaths in the first week, the highest proportion of deaths occurred on the first day (first 24 hours, 38.8%), followed by day 2 (24-48 hours, 12.3%). Considering weekly mortality within the first month (n = 16 studies), the first week had the highest mortality (71.7%). Based on data from 46 studies, the highest proportion of deaths occurred on day 1 (39.5%), followed closely by days 2-7 (36.8%), with the remainder occurring between days 8 and 28 (23.0%). In terms of causes, birth asphyxia accounted for the highest proportion of deaths on day 1 (68.1%), severe infection between days 2 and 7 (48.1%), and diarrhea between days 8 and 28 (62.7%). Due to heterogeneity, neonatal morbidity data were described narratively. The mean critical appraisal score of all studies was 84% (SD = 16%).Conclusion: newborns experience high mortality throughout the entire postnatal period, with the highest mortality rate in the first week, particularly on the first day. Ensuring regular high-quality postnatal visits, particularly within the first week after birth, is paramount to reduce neonatal mortality and severe morbidity.</p

Timing of maternal mortality and severe morbidity during the postpartum period: a systematic review

Objective: the objective of this review was to determine the timing of overall and cause-specific maternal mortality and severe morbidity during the postpartum period.Introduction: many women continue to die or experience adverse health outcomes in the postpartum period; however, limited work has explored the timing of when women die or present complications during this period globally.Inclusion criteria: this review considered studies that reported on women after birth up to 6 weeks postpartum and included data on mortality and/or morbidity on the first day, days 2-7, and days 8-42. Studies that reported solely on high-risk women (eg, those with antenatal or intrapartum complications) were excluded, but mixed population samples were included (eg, low-risk and high-risk women).Methods: MEDLINE, Embase, Web of Science, and CINAHL were searched for published studies on December 20, 2019, and searches were updated on May 11, 2021. Critical appraisal was undertaken by 2 independent reviewers using standardized critical appraisal instruments from JBI. Quantitative data were extracted from included studies independently by at least 2 reviewers using a study-specific data extraction form. Quantitative data were pooled, where possible. Identified studies were used to obtain the summary estimate (proportion) for each time point. Maternal mortality was calculated as the maternal deaths during a given period over the total number of maternal deaths known during the postpartum period. For cause-specific analysis, number of deaths due to a specific cause was the numerator, while the total number of women who died due to the same cause in that period was the denominator. Random effects models were run to pool incidence proportion for relative risk of overall maternal deaths. Subgroup analysis was conducted according to country income classification and by date (ie, data collection before or after 2010). Where statistical pooling was not possible, the findings were reported narratively.Results: a total of 32 studies reported on maternal outcomes from 17 reports, all reporting on mixed populations. Most maternal deaths occurred on the first day (48.9%), with 24.5% of deaths occurring between days 2 and 7, and 24.9% occurring between days 8 and 42. Maternal mortality due to postpartum hemorrhage and embolism occurred predominantly on the first day (79.1% and 58.2%, respectively). Most deaths due to postpartum eclampsia and hypertensive disorders occurred within the first week (44.3% on day 1 and 37.1% on days 2-7). Most deaths due to infection occurred between days 8 and 42 (61.3%). Due to heterogeneity, maternal morbidity data are described narratively, with morbidity predominantly occurring within the first 2 weeks. The mean critical appraisal score across all included studies was 85.9% (standard deviation = 13.6%).Conclusion: women experience mortality throughout the entire postpartum period, with the highest mortality rate on the first day. Access to high-quality care during the postpartum period, including enhanced frequency and quality of postpartum assessments during the first 42 days after birth, is essential to improving maternal outcomes and to continue reducing maternal mortality and morbidity worldwide.Systematic review registration number: PROSPERO CRD42020187341.</p

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

<div><p>Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in <i>THAP1</i> [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, <i>THAP1</i> downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the <i>in vivo</i> effect of a heterozygote <i>Thap1</i> C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence in the pathophysiology of several forms of inherited dystonia.</p></div

Cortico-striatal synaptic plasticity is altered in <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} derived slices.

<p><b>(A)</b><i>Thap1</i>^<i>+/-</i> mice are deficient in synaptically-induced LTD in dorsolateral striatum compared to wildtype controls (A₁; <i>p</i> < .05), while LTP in the dorsomedial region is intact (A₂). Representative excitatory postsynaptic potential (EPSP) traces in this and panel B were averaged over the baseline period (thin line) and over the final 5 min of recording (thick line), color coded to the graph. Calibration for these and all other traces: 1 mV / 5 ms. <b>(B)</b> In <i>Thap1</i>^{<i>C54Y/+</i>} mice, LTD was not significantly reduced (B₁), but LTP was deficient (B₂; p < .05). Note that wildtype data are the same as for panel A, and that all genotypes were analyzed together. <b>(C)</b> Paired-pulse ratio was not altered in <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} mice. The traces show averaged EPSPs recorded at inter-stimulus interval = 50 ms (thin and thick lines show responses to first and second stimuli, respectively). All graphs show group means ± SEM, and the number of slices/mice for each group are shown in parentheses. Data were analyzed by ANOVAs performed over the final 5 minutes of recording (panels A and B) or on averaged paired-pulse data for each interval (panel C), followed where appropriate by Newman-Keuls <i>post-hoc</i> tests. *p<0.05 See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007169#pgen.1007169.s012" target="_blank">S9 Table</a>.</p

Key constituents of the eIF2α signaling pathway are down-regulated in the brains of <i>Thap1</i>^<i>+/-</i> mice as compared to WT.

<p><b>(A)</b> mRNA expression gene profiles of key genes from the eIF2α signaling pathway were assayed with quantitative real-time PCR (RT-qPCR) using cerebellar samples. Data normalized relative to WT. Data are presented as means ± Standard Error of the Mean (SEM); n = 8 for each genotype and brain region with separate littermate WT controls, <i>Student’s t test</i> (*p<0.05; ** p<0.01; *** p<0.005). See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007169#pgen.1007169.s012" target="_blank">S9 Table</a>. <b>(B)</b> Levels of protein expression in the striatum and cerebellum of P1 <i>THAP1</i>^<i>+/-</i> mice relative to WT were assayed by western blot. Densitometry measurements (arbitrary units) are normalized to the housekeeping gene GAPDH, or for phosphoproteins, relative to GAPDH and their respective holoprotein level. Data are presented as means ± SEM; n = 4 for each genotype and region with separate, littermate WT controls, <i>Student’s t test</i>. *p<0.05. See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007169#pgen.1007169.s012" target="_blank">S9 Table</a>.</p

Inhibition of eIF2α phosphatase rescues mGluR-LTD, but not synaptically-induced LTD.

<p>The summary graphs in the right panels show mean ± SEM for the final 5 min of recording. <b>(A)</b> LTD after treatment with group 1 agonist DHPG (100 μM, applied during the gap in the graph) was reduced in <i>Thap1</i>^<i>+/-</i> slices, and pretreatment with Sal003 (20 μM) (eIF2α phosphatase inhibitor) rescued LTD in <i>Thap1</i>^<i>+/-</i> slices. <b>(B)</b> In high frequency stimulation (HFS)-induced LTD, Sal003 (10 μM) failed to reverse the deficit observed in <i>Thap1</i>^<i>+/-</i> slices. Numbers in parentheses indicate number of slices/number of mice. Representative traces are shown during baseline period (solid lines) and at the end of the recording period (dashed lines). Calibrations: 1 mV / 5 ms. Asterisks indicate <i>p</i> < .05 (*) or p < .01 (**) by ANOVAs followed by Newman-Keuls <i>post-hoc</i> tests. See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007169#pgen.1007169.s012" target="_blank">S9 Table</a>.</p

Top canonical pathways and gene ontology terms enriched in striatum and cerebellum of <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} relative to WT.

<p><b>(A,B)</b> Top canonical pathways as determined by IPA analysis, and <b>(C,D)</b> DAVID Gene Ontology (GO) terms show an enrichment of biological process based on the list of significant DEGs (DEseq p < 0.05) in the striatum of <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} relative to WT. <b>(E,F)</b> Top canonical pathways and <b>(G,H)</b> DAVID GO terms based on the list of significant DEGs in the cerebellum of <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} relative to WT.</p

Global analysis of differential gene expression in striatum and cerebellum of <i>Thap1</i>^<i>+/-</i> or <i>Thap1</i>^{<i>C54Y/+</i>} vs WT.

<p>RNA-Seq was used to identify differentially expressed genes (DEGs) in the heterozygote <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^<i>C54Y</i> P1 striatum and cerebellum as compared to WT. Diagrams show number of total DEGs as well as the number of up- or down-regulated genes in the <b>(A)</b> <i>Thap1</i>^<i>+/-</i> striatum vs WT <b>(B)</b> <i>Thap1</i>^<i>C54Y</i> striatum vs WT. <b>(C)</b> Venn diagrams show the number of overlapping DEGs (total, up-regulated or down-regulated) between <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} relative to WT striatum. Diagrams show number of total DEGs as well as the number of up- or down-regulated genes in the <b>(D)</b> <i>Thap1</i>^<i>+/-</i> cerebellum vs WT <b>(E)</b> <i>Thap1</i>^{<i>C54Y/+</i>} cerebellum vs WT. <b>(F)</b> Venn diagrams show the number of overlapping DEGs (total, up-regulated or down-regulated) between <i>Thap1</i>^<i>+/-</i> and <i>Thap1</i>^{<i>C54Y/+</i>} relative to WT cerebellum. Cogged gears in panels A, B, D and E represent the number and the direction of the differentially expressed genes for each genotype and brain region, as follows: up-regulated genes (turquoise color, upward right arrow); down-regulated genes (dark blue color, downward left arrow); total [number] of genes (purple color, downward right arrow).</p

Tunicamycin challenge in P4 <i>Thap1</i>^<i>+/-</i> and WT pups increases eiF2α signaling pathway proteins and reveals genotype-dependent differences in striatum and cerebellum.

<p>Western blot analysis of <b>(A)</b> striatal and <b>(B)</b> cerebellar lysates from <i>Thap1</i>^<i>+/-</i> and WT littermates for BiP, ATF4 and CHOP were performed 24 hrs after subcutaneous tunicamycin (TM) diluted in 150mM dextrose (or dextrose-only control; DEX). Protein expression levels represent normalization to the housekeeping gene GAPDH. Data are presented as means ± SEM; n = 5 for each genotype and region, data normalized to WT (dextrose-only) controls. Statistical differences were assessed by two-way ANOVAs with Tukey’s <i>post hoc</i> tests. *<i>p</i> < 0.05; **<i>p</i> < 0.01; ***<i>p</i> < 0.001. See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007169#pgen.1007169.s012" target="_blank">S9 Table</a>.</p