Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Rationale and design of the effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV) trial.

BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.

Induction of labor and cesarean birth in lower-risk nulliparous women at term: A retrospective cohort study.

OBJECTIVE: To evaluate whether induction of labor (IOL) is associated with cesarean birth (CB) and perinatal mortality in uncomplicated first births at term compared with expectant management outside the confines of a randomized controlled trial. METHODS: Population-based retrospective cohort study of all births in Victoria, Australia, from 2010 to 2018 (n = 640,191). Preliminary analysis compared IOL at 37 weeks with expectant management at that gestational age and beyond for uncomplicated pregnancies. Similar comparisons were made for IOL at 38, 39, 40, and 41 weeks of gestation and expectant management. The primary analysis repeated these comparisons, limiting the population to nulliparous women with uncomplicated pregnancies and excluding those with a medical indication for IOL. We compared perinatal mortality between groups using Chi-square tests and multivariable logistic regression for all other comparisons. Adjusted odds ratios and 99% confidence intervals were reported. p < 0.01 denoted statistical significance. RESULTS: Among nulliparous, uncomplicated pregnancies at ≥37 weeks of gestation in Victoria, IOL increased from 24.6% in 2010 to 30.0% in 2018 (p < 0.001). In contrast to the preliminary analysis, the primary analysis showed that IOL in lower-risk nulliparous women was associated with increased odds of CB when performed at 38 (aOR 1.23(1.13-1.32)), 39 (aOR 1.31(1.23-1.40)), 40 (aOR 1.42(1.35-1.50)), and 41 weeks of gestation (aOR 1.43(1.35-1.51)). Perinatal mortality was rare in both groups and non-significantly lower in the induced group at most gestations. DISCUSSION: For lower-risk nulliparous women, the odds of CB increased with IOL from 38 weeks of gestation, along with decreased odds of perinatal mortality at 41 weeks only.

Lipidomic analysis of Porphyromonas gingivalis reveals novel glycerol bisphosphoceramide, phosphatidyl-, and phosphoglycerol dipeptide lipid families.

Porphyromonas gingivalis, like other members of the phylum Bacteroidetes (synonym Bacteroidota), synthesizes several classes of dihydroceramides and peptidolipids. Using a similar strategy as that recently used to delimit the lipidome of its close relative Bacteroides fragilis, we applied linear ion trap multiple-stage mass spectrometry (linear ion trap MSn) with high-resolution mass spectrometry, to structurally characterize the complete lipidome of P. gingivalis and compare it to B. fragilis. This analysis discovered that the P. gingivalis lipidome consists of several previously unidentified lipid families, including dihydroceramide-1-phosphophate, acylated dihydroceramide-1-phosphophate, phosphoglycerol glycylserine lipid, and bis(phosphodihydroceramide) glycerol. Interestingly, we also found a novel sphingolipid family containing a polyunsaturated long-chain base, and a new lipoglycylserine phosphatic acid containing unsaturated acyl chains not reported for the lipid family. The comprehensive coverage of the lipidome of P. gingivalis conducted in this study has revealed more than 140 lipid species including several novel lipids in over 20 lipid families/subfamilies.

Inhibitory effect of Porphyromonas gingivalis-derived phosphoethanolamine dihydroceramide on acid ceramidase expression in oral squamous cells.

The maintenance of diminished acid ceramidase (ASAH1) gene expression leading to the accumulation of antiproliferative intracellular ceramides in oral squamous cell carcinoma (OSCC) has emerged as a prospective oral cancer therapeutic regimen. Our published study demonstrated that the key periodontal pathogen Porphyromonas gingivalis downregulates the expression patterns of ASAH1 mRNA in normal epithelial cells in vitro. Therefore, P. gingivalis may also beneficially diminish the expression of ASAH1 in OSCC. Because a uniquely structured P. gingivalis-derived phosphoethanolamine dihydroceramide (PEDHC) inhibits the proliferation of normal human fibroblasts, this study aimed to test the effect of PEDHC on the survival of human oral squamous OECM-1 cells in vitro. We demonstrated that the P. gingivalis dihydroceramide-null (ΔPG1780) strain upregulates the expression of ASAH1 mRNA and promotes aggressive proliferation and migration of OECM-1 cells compared to the parent P. gingivalis-W83 strain. In addition, the intracellular concentration of ceramides was dramatically elevated in OECM-1 cells exposed to PEDHC in vitro. Furthermore, PEDHC inhibited expression patterns of ASAH1 mRNA as well as some genes associated with degradation of the basement membranes and extracellular matrix, for example, MMP-2, ADAM-17 and IL-6, in OECM-1 cells. Altogether, these data indicated that PEDHC produced by P. gingivalis inhibits acid ceramidase expression, promotes intracellular ceramide accumulation and suppresses the survival and migration of OSCC cells in vitro. Further studies are needed to determine molecular mechanisms of PEDHC-mediated inhibitory effect(s) on OSCC using in vivo models of oral cancer.

Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking. METHODS: The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. RESULTS: A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68-0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04). CONCLUSIONS: Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT02867813 and NCT03080935.

Fetal surveillance from 39 weeks' gestation to reduce stillbirth in South Asian-born women.

BACKGROUND: In July 2017, the State of Victoria's largest maternity service implemented a new clinical guideline to reduce the rates of stillbirth at term for South Asian women. OBJECTIVE: This study aimed to evaluate the impact of offering fetal surveillance from 39 weeks to South Asian-born women on rates of stillbirth and neonatal and obstetrical interventions. STUDY DESIGN: This was a cohort study of all women receiving antenatal care at 3 large metropolitan university-affiliated teaching hospitals in Victoria, who gave birth in the term period between January 2016 and December 2020. Differences in rates of stillbirth, neonatal deaths, perinatal morbidities, and interventions after July 2017 were determined. Multigroup interrupted time-series analysis was used to assess changes in rates of stillbirth and induction of labor. RESULTS: A total of 3506 South Asian-born women gave birth before, and 8532 after the change in practice. There was a 64% reduction in term stillbirth (95% confidence interval, 87% to 2%; P=.047) after the change in practice from 2.3 per 1000 births to 0.8 per 1000 births. The rates of early neonatal death (3.1/1000 vs 1.3/1000; P=.03) and special care nursery admission (16.5% vs 11.1%; P<.001) also decreased. There were no significant differences in admission to the neonatal intensive care unit, 5-minute Apgar score <7, or birthweight, or differences in the trends of induction of labor per month. CONCLUSION: Fetal monitoring from 39 weeks may offer an alternative to routine earlier induction of labor to reduce the rates of stillbirth without causing an increase in neonatal morbidity and attenuating trends in obstetrical interventions.

Elective induction of labour at full-term gestations and childhood school outcomes.

AIM: To explore the association between induction of labour at full-term gestations in low-risk nulliparous women and childhood school outcomes. METHODS: A retrospective whole-of-population cohort study linking perinatal data to educational test scores at grades 3, 5 and 7 in Victoria, Australia. Low-risk nulliparous women with singleton pregnancies induced at 39 and 40 weeks without a medical indication were compared to those expectantly managed from that week of gestation. Multivariable logistic regressions were used as well as generalised estimating equations on longitudinal data. RESULTS: At 39 weeks, there were 3687 and 103 164 infants in the induction and expectant arms, respectively. At 40 weeks' gestation, there were 7914 and 70 280 infants, respectively. Infants born to nulliparous women induced at 39 weeks' gestation had significantly poorer educational outcomes at grade 3 (adjusted odds ratio (aOR) = 1.39, 95% confidence interval (CI): 1.13-1.70) but not grades 5 (aOR = 1.05, 95% CI: 0.84-1.33) and 7 (aOR = 1.07, 95% CI: 0.81-1.40) compared to those expectantly managed. Infants born to nulliparous women induced at 40 weeks had comparable educational outcomes at grade 3 (aOR = 1.06, 95% CI: 0.90-1.25) but poorer educational outcomes at grades 5 (aOR = 1.23, 95% CI: 1.05-1.43) and 7 (aOR = 1.23, 95% CI: 1.03-1.47) compared to those expectantly managed. CONCLUSIONS: There were inconsistent associations between elective induction of labour at full-term gestations in low-risk nulliparous women and impaired childhood school outcomes.

Incidence and management of premature rupture of membranes in Victoria, Australia: A retrospective cohort study of 636 590 births between 2009 and 2017.

BACKGROUND: Premature rupture of membranes (PROM) is a complication affecting 7-12% of pregnancies in which fetal chorioamniotic membranes rupture before labour begins. Preterm PROM (PPROM) (ie <37 weeks gestation) precedes one-third of preterm births, exposing the fetus to increased morbidity from placental abruption, respiratory distress syndrome and sepsis. AIM: To analyse trends in the incidence and mode of birth in preterm and term PROM in Victoria, Australia between 2009 and 2017. MATERIALS AND METHODS: This retrospective population-based cohort study included all singleton pregnancies from 2009 to 2017. We examined women with PROM (both <37 weeks (PPROM) and at term). Management was assessed in three categories: (a) expectant management; (b) induction of labour (IOL); and (c) elective caesarean section (elCS). A multinomial logistic regression model was used to adjust for confounders influencing the choice of management. RESULTS: Of 636 590 singleton pregnancies, 52 669 (8.3%) births with PROM at term (42 439; 6.7%) or PPROM (10 230; 1.6%) were identified. Of these, the majority were managed expectantly (n = 22 726; 43.1%), or with IOL (25 931; 49.2%). While elCS represented only 7.6% of these cases (n = 4012), its use rose consistently from 2009 to 2017 for PROM at term and PPROM alike. For women with PPROM at 34-36 weeks the odds of elCS increased by 5% annually (adjusted odds ratio (aOR) 1.05; 95% CI 1.02-1.08) and 2% for IOL (aOR 1.02; 95% CI 1.00-1.05) vs expectant management. CONCLUSIONS: The use of elCS and IOL in PPROM is rising in Victoria, particularly between 34 and 36 completed weeks of pregnancy. Research is needed to determine the drivers for this increase.

The evolution of the diagnostic criteria of preeclampsia-eclampsia.

As the understanding of the pathophysiology of preeclampsia has improved, its diagnostic criteria have evolved. The classical triad of hypertension, edema, and proteinuria has become hypertension and organ dysfunction-renal, hepatic, neurologic, hematological, or uteroplacental. However, the most recent definitions have largely been based off consensus and expert opinion, not primary research. In this review, we explore how the criteria have evolved, particularly through the second half of the 20th and the beginning of the 21st century and offer a critical appraisal of the evidence that has led the criteria to where they stand today. Some key themes are the following: the debate between having a simple and convenient blood pressure cutoff vs a blood pressure cutoff that accounts for influencing factors such as age and weight; whether a uniform blood pressure threshold, a rise in blood pressure, or a combination is most discriminatory; whether existing evidence supports blood pressure and proteinuria thresholds in diagnosing preeclampsia; and whether using flow-charts and decision trees might be more appropriate than a single set of criteria. We also discuss the future of a preeclampsia diagnosis. We challenge the move toward a broad (vs restrictive) diagnosis, arguing instead for criteria that directly relate to the prognosis of preeclampsia and the response to treatments.

The 5-minute Apgar score and childhood school outcomes.

AIM: To examine the association between Apgar score at 5 min and childhood developmental and educational outcome. METHODS: A population-based data linkage study of births ≥37 weeks' gestation linked to developmental outcomes at preparatory school and educational outcomes at school grades 3, 5 and 7 in Victoria, Australia. Multivariable logistic regressions and generalised estimating equations were used. RESULTS: There were 167,126 singleton infants with developmental results and 392,933 singleton infants with at least one educational result. There was an inverse relationship between Apgar score at 5 min and poor developmental and educational outcomes, with the worst outcomes among Apgar scores of 0-3. Apgar scores of 7, 8 and 9 were all associated with poorer developmental outcomes (aOR = 1.31, 95% CI: 1.12-1.54; aOR = 1.17, 95% CI: 1.05-1.29; aOR = 1.08, 95% CI: 1.02-1.13 respectively), while Apgar scores of 7 and 8 were associated with poorer educational outcomes at grades 3, 5, and 7. With progression through grades 3, 5, and 7, the extent of the difference in educational outcomes diminished (e.g. for Apgar scores of 0-3: aOR = 3.33, 95% CI: 1.85-6.00 in grade 3 and aOR = 1.49, 95% CI: 0.75-2.96 in grade 7). CONCLUSION: Apgar scores below 10 at 5 min are associated with poorer developmental and educational outcomes in school.

PPAD Activity Promotes Outer Membrane Vesicle Biogenesis and Surface Translocation by Porphyromonas gingivalis.

Many bacteria switch between a sessile and a motile mode in response to environmental and host-related signals. Porphyromonas gingivalis, an oral anaerobe implicated in the etiology of chronic periodontal disease, has long been described as a nonmotile bacterium. And yet, recent studies have shown that under certain conditions, P. gingivalis is capable of surface translocation. Considering these findings, this work aimed to increase our understanding of how P. gingivalis transitions between sessile growth and surface migration. Here, we show that the peptidylarginine deiminase secreted by P. gingivalis (PPAD), an enzyme previously shown to be upregulated during surface translocation and to constrain biofilm formation, promotes surface translocation. In the absence of PPAD, the production of outer membrane vesicles (OMVs) was drastically reduced. In turn, there was a reduction in gingipain-mediated proteolysis and a reduced zone of hydration around the site of inoculation. Transcriptome sequencing (RNA-Seq) and metabolomics analyses also showed that these changes corresponded to a shift in arginine metabolism. Overall, this report provides new evidence for the functional relevance of PPAD and proteases, as well as the importance of PPAD activity in OMV biogenesis and release. Our findings support the model that citrullination is a critical mechanism during lifestyle transition between surface-attached growth and surface translocation by modulating OMV-mediated proteolysis and arginine metabolism.IMPORTANCE Gram-negative bacteria produce nanosized OMVs that are actively released into their surroundings. The oral anaerobe P. gingivalis is prolific in OMV production, and many of the proteins packaged in these vesicles are proteolytic or protein-modifying enzymes. This includes key virulence determinants, such as the gingipains and PPAD (a unique peptidylarginine deiminase). Here, we show that PPAD activity (citrullination) is involved in OMV biogenesis. The study revealed an unusual mechanism that allows this bacterium to transform its surroundings. Since OMVs are detected in circulation and in systemic tissues, our study results also support the notion that PPAD activity may be a key factor in the correlation between periodontitis and systemic diseases, further supporting the idea of PPAD as an important therapeutic target.

Sphingolipid-Containing Outer Membrane Vesicles Serve as a Delivery Vehicle To Limit Macrophage Immune Response to Porphyromonas gingivalis.

Sphingolipids (SLs) are essential structural components of mammalian cell membranes. Our group recently determined that the oral anaerobe Porphyromonas gingivalis delivers its SLs to host cells and that the ability of P. gingivalis to synthesize SLs limits the elicited host inflammatory response during cellular infection. As P. gingivalis robustly produces outer membrane vesicles (OMVs), we hypothesized that OMVs serve as a delivery vehicle for SLs, that the SL status of the OMVs may impact cargo loading to OMVs, and that SL-containing OMVs limit elicited host inflammation similar to that observed by direct bacterial challenge. Transwell cell culture experiments determined that in comparison to the parent strain W83, the SL-null mutant elicited a hyperinflammatory immune response from THP-1 macrophage-like cells with elevated tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL-1ß), and IL-6. Targeted assessment of Toll-like receptors (TLRs) identified elevated expression of TLR2, unchanged TLR4, and elevated expression of the adaptor molecules MyD88 and TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing beta interferon) by SL-null P. gingivalis No significant differences in gingipain activity were observed in our infection models, and both strains produced OMVs of similar sizes. Using comparative two-dimensional gel electrophoresis, we identified differences in the protein cargo of the OMVs between parent and SL-null strain. Importantly, use of purified OMVs recapitulated the cellular inflammatory response observed in the transwell system with whole bacteria. These findings provide new insights into the role of SLs in P. gingivalis OMV cargo assembly and expand our understanding of SL-OMVs as bacterial structures that modulate the host inflammatory response.

Factors associated with SARS-CoV-2 infection in patients attending an acute hospital ambulatory assessment unit.

To describe the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in mild-to-moderate patients attending for assessment. This observational study was conducted in a Model 4 tertiary referral center in Ireland. All patients referred for SARS-CoV-2 assessment over a 4-week period were included. Patient demographics, presenting symptoms, comorbidities, medications, and outcomes (including length of stay, discharge, and mortality) were collected. Two hundred and seventy-nine patients were assessed. These patients were predominantly female (62%) with a median age of 50 years (SD 16.9). Nineteen (6.8%) patients had SARS-CoV-2 detected. Dysgeusia was associated with a 16-fold increased prediction of SARS-CoV-2 positivity (p = .001; OR, 16.8; 95% CI, 3.82-73.84). Thirteen patients with SARS-COV-2 detected (68.4%) were admitted, in contrast with 38.1% (99/260) of patients with SARS-CoV-2 non-detectable or not tested (p = .001). Female patients were more likely to be hospitalized (p = .01) as were current and ex-smokers (p = .05). We describe olfactory disturbance and fever as the main presenting features in SARS-CoV-2 infection. These patients are more likely to be hospitalized with increased length of stay; however, they make up a minority of the patients assessed. "Non-detectable" patients remain likely to require prolonged hospitalization. Knowledge of predictors of hospitalization in a "non-detectable" cohort will aid future planning and discussion of patient assessment in a SARS-CoV-2 era.

Trends in singleton preterm birth in Victoria, 2007 to 2017: A consecutive cross-sectional study.

INTRODUCTION: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries preterm birth rates are increasing, largely as a result of increases in iatrogenic preterm birth, whereas in other countries rates are stable or even declining. The objective of the study is to describe trends in singleton preterm births in Victoria from 2007 to 2017 in relation to trends in perinatal mortality to identify opportunities for improvements in clinical care. MATERIAL AND METHODS: We conducted a consecutive cross-sectional study in all women with a singleton pregnancy giving birth at ≥20 weeks of pregnancy in Victoria, Australia, between 2007 and 2017, inclusive. Rates of preterm birth and perinatal mortality were calculated and trends were analyzed in all pregnancies, in pregnancies complicated by fetal growth problems, hypertension, (pre)eclampsia or prelabor rupture of membranes (PROM), and in (low-risk) pregnancies not complicated by any of these conditions. RESULTS: There were 811 534 singleton births between 2007 and 2017. Preterm birth increased from 5.9% (4074 births) to 6.4% (4893 births; P < .001), due to an increase in iatrogenic preterm birth from 2.5% (1730 births) to 3.6% (2730 births; P < .001). Comparable trends were seen in pregnancies complicated by fetal growth problems and hypertension and in pregnancies not complicated by small for gestational age (SGA), hypertension, (pre)eclampsia or PROM (all P < .001). In pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM the perinatal mortality rate from 20 weeks of gestation fell (13 to 12 per 1000 births; P < .001). In pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM there was no significant change in the perinatal mortality from 28 weeks and no decrease in the preterm weekly prospective stillbirth risk. CONCLUSIONS: The singleton preterm birth rate in Victoria is increasing, driven by an increase in iatrogenic preterm birth, both in pregnancies complicated by SGA and hypertension, and in pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM. While perinatal mortality decreased in the pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM, no significant reduction in perinatal mortality from 28 weeks or in preterm weekly prospective stillbirth risk was noted in the pregnancies not complicated by any of these conditions.

Does detection of fetal growth restriction improve neonatal outcomes?

AIM: Timely delivery of fetal growth restriction (FGR) is a balance between avoiding stillbirth and minimising prematurity. We sought to assess the neonatal outcomes for babies suspected of FGR, both true and false positives. METHODS: This population cohort study examined all singleton births in Victoria, Australia from 2000 to 2017 (n = 1 231 415). Neonatal morbidities associated with neonatal intensive care unit (NICU) admission were assessed for babies born ≥32 weeks' with severe FGR (<3rd centile) and babies with birthweight ≥10th centile who were iatrogenically delivered for suspected FGR. RESULTS: Babies with severe FGR iatrogenically delivered for suspected FGR were more likely to require NICU admission than babies with severe FGR who were not detected (3.0% vs. 1.1%, P < 0.001). After adjusting for potential confounders, the odds of NICU admission were increased (adjusted odds ratio (aOR) = 3.00, 95% confidence interval = 2.45-3.67; P < 0.001). Rates of NICU admission were also higher in ≥10th centile babies iatrogenically delivered for suspected FGR than for ≥10th centile babies who entered labour spontaneously (1.8% vs. 0.5%, P < 0.001). After adjustments, the odds of NICU admission were increased (aOR = 3.91, 95% confidence interval = 3.40-4.49; P < 0.001). NICU admissions were associated with morbidities related to iatrogenic prematurity. CONCLUSIONS: Detection and planned delivery of FGR reduces stillbirth but may be associated with increased neonatal morbidity related to iatrogenic prematurity.

Preventing harm: A balance measure for improving the detection of fetal growth restriction.

BACKGROUND: Increasing the detection of fetal growth restriction (FGR), while reducing stillbirth, also leads to unnecessary early intervention, and associated morbidity, for normally grown babies who are incorrectly suspected of FGR. AIMS: We sought to design a balance measure that addresses the specificity of FGR detection. METHODS: A retrospective cohort study on all singleton births ≥32 weeks gestation in 2016 and 2017 in Victoria. We compared two balance measures for the detection of FGR, defined as the proportion of all babies iatrogenically delivered before 39 weeks gestation for suspected FGR that had a birthweight ≥10th centile (balance measure 1) or ≥25th centile (balance measure 2). Hospital level performance on each balance measure was derived and compared to an existing performance measure for severe FGR detection in Victoria. RESULTS: Of the 38 hospitals analysed, 12 (32%) had a favourable performance on an existing indicator of FGR detection, seven (18%) hospitals had a favourable performance on balance measure 1, and 15 (39%) had a favourable performance on balance measure 2. There was a moderate correlation between hospital performance on the existing indicator and on balance measure 1 (r = 0.447, P = 0.005) but not balance measure 2 (r = -0.063, P = 0.71). There was no difference in perinatal mortality between high performing hospitals and low performing hospitals. CONCLUSION: Introducing a balance measure into routine reporting may bring greater awareness to the unintended harm associated with increased detection of FGR.

The addition of fetal scalp blood lactate measurement as an adjunct to cardiotocography to reduce caesarean sections during labour: The Flamingo randomised controlled trial.

BACKGROUND: Fetal scalp blood sampling for lactate measurement (FBSLM) is sometimes used to assist in identification of the need for expedited birth in the presence of an abnormal cardiotocograph (CTG). However, there is no randomised controlled trial evidence to support this. AIM: To determine whether adding FBSLM reduces the risk of birth by emergency caesarean section in labours complicated by an abnormal CTG, compared with CTG without FBS. MATERIAL AND METHODS: Labouring women at a tertiary maternity hospital in Melbourne, Australia with a singleton, cephalic presentation, at ≥37 weeks gestation with an abnormal CTG pattern were randomised to the intervention (n = 61), with intermittent FBSLM in addition to CTG monitoring, or control (CTG without FBS, n = 62). The primary outcome was rate of birth by caesarean section. Secondary outcomes included overall operative birth and fetal and neonatal safety endpoints. TRIAL REGISTRATION: ACTRN12611000172909. RESULTS: The smaller than anticipated sample was unable to demonstrate an effect from adding FBSLM to CTG monitoring on birth by caesarean section vs monitoring by CTG without FBS (25/61 and 28/62 respectively, P = 0.64, risk ratio 0.91, 95% confidence intervals 0.60-1.36). One newborn infant in the CTG group met the criteria for the composite neonatal outcome of death or serious outcome, neonatal encephalopathy, five-minute Apgar score < 4, neonatal resuscitation, admission to neonatal intensive care unit for 96 h or more. CONCLUSION: We were unable to provide robust evidence of the effectiveness of FBSLM to improve the specificity of the CTG in the assessment of fetal wellbeing.

Trends in preterm birth in twin pregnancies in Victoria, Australia, 2007-2017.

BACKGROUND: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries, the preterm birth rate in women with a multiple pregnancy is increasing, mostly due to an increase in iatrogenic preterm birth. AIMS: To investigate trends in preterm birth in twin pregnancies in Victoria, Australia, in relation to maternal and perinatal complications. MATERIALS AND METHODS: We conducted a retrospective population-based cohort study in all women with a twin pregnancy who delivered at or after 20 weeks of gestation in the state of Victoria, Australia between 2007 and 2017. Annual spontaneous and iatrogenic preterm birth rates were calculated and trends analysed. Incidence of adverse pregnancy outcomes, maternal complications and risk factors for preterm birth were analysed. RESULTS: We studied 12 757 women with a twin pregnancy. Between 2007 and 2017 the preterm birth rate increased from 641/1231 (52%) to 803/1158 (69%), mainly due to an increase in iatrogenic preterm birth from 342/1231 (28%) to 567/1158 (49%). This was irrespective of the presence of pregnancy complications. Our study showed neither a decrease in perinatal mortality from 28 weeks of gestation nor in preterm average weekly prospective stillbirth risk. CONCLUSION: Preterm birth rates in twins in Victoria are increasing, mainly driven by an increase in iatrogenic preterm birth. This occurred both in complicated and non-complicated twin pregnancies, and has not been accompanied by reduction in perinatal mortality from 28 weeks.

Association Between Iatrogenic Delivery for Suspected Fetal Growth Restriction and Childhood School Outcomes.

Importance: Timely delivery of infants suspected of having fetal growth restriction (FGR) is a balance between preventing stillbirth and minimizing prematurity, particularly because many infants with suspected FGR have normal growth. Objective: To explore the association between iatrogenic delivery for suspected FGR and childhood school outcomes. Design, Setting, and Participants: A retrospective whole-population cohort study linking perinatal data from births 32 weeks' or more gestation between January 1, 2003, to December 31, 2013, to developmental and educational test scores at preparatory school, and at school grades 3, 5, and 7 in Victoria, Australia. Follow-up was concluded in 2019. Exposures: Suspicion or nonsuspicion of FGR, presence or absence of iatrogenic delivery (defined as early induction of labor or cesarean delivery prior to labor) for suspected FGR, and presence or absence of small for gestational age (SGA). Main Outcomes and Measures: The coprimary outcomes were being in the bottom 10th percentile on 2 or more of 5 developmental domains at school entry and being below the national minimum standard on 2 or more of 5 educational domains in grades 3, 5, or 7. Results: In the birth population of 705 937 infants, the mean gestation at birth was 39.1 (SD, 1.5) weeks and the mean birth weight was 3426 (SD, 517) grams. The birth population linked to 181 902 children with developmental results and 425 717 children with educational results. Compared with infants with severe SGA (birth weight <3rd percentile) not suspected of having FGR, infants with severe SGA delivered for suspected FGR were born earlier (mean gestation, 37.9 weeks vs 39.4 weeks). They also had a significantly increased risk of poor developmental outcome at school entry (16.2% vs 12.7%; absolute difference, 3.5% [95% CI, 0.5%-6.5%]); adjusted odds ratio [aOR], 1.36 [95% CI, 1.07-1.74]) and poor educational outcomes in grades 3, 5, and 7 (for example, in grade 7: 13.4% vs 10.5%; absolute difference, 2.9% [95% CI, 0.4%-5.5%]); aOR, 1.33 [95% CI, 1.04-1.70]). There was no significant difference between infants with normal growth (birth weight ≥10th percentile) delivered for suspected FGR and those not suspected of having FGR in developmental outcome (8.6% vs 8.1%; absolute difference, 0.5% [95% CI, -1.1% to 2.0%]); aOR, 1.17 [95% CI, 0.95-1.45]) or educational outcome in grade 3, 5 or 7, despite being born earlier (mean gestation, 38.0 weeks vs 39.1 weeks). Conclusions and Relevance: In this exploratory study conducted in Victoria, Australia, iatrogenic delivery of infants with severe SGA due to suspected FGR was associated with poorer school outcomes compared with infants with severe SGA not suspected of having FGR. Iatrogenic delivery of infants with normal growth due to suspected FGR was not associated with poorer school outcomes compared with infants with normal growth not suspected of having FGR.