Systematic Review of Clinical Prediction Models for the Risk of Emergency Caesarean Births.

BACKGROUND: Globally, caesarean births (CB), including emergency caesareans births (EmCB), are rising. It is estimated that nearly a third of all births will be CB by 2030. OBJECTIVES: Identify and summarise the results from studies developing and validating prognostic multivariable models predicting the risk of EmCBs. Ultimately understanding the accuracy of their development, and whether they are operationalised for use in routine clinical practice. SEARCH STRATEGY: Studies were identified using databases: MEDLINE, CINAHL, Cochrane Central and Scopus with a search strategy tailored to models predicting EmCBs. SELECTION CRITERIA: Prospective studies developing and validating clinical prediction models, with two or more covariates, to predict risk of EmCB. DATA COLLECTION AND ANALYSIS: Data were extracted onto a proforma using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). RESULTS: In total, 8083 studies resulted in 56 unique prediction modelling studies and seven validating studies, with a total of 121 different predictors. Frequently occurring predictors included maternal height, maternal age, parity, BMI and gestational age. PROBAST highlighted 33 studies with low overall bias, and these all internally validated their model. Thirteen studies externally validated; only eight of these were graded an overall low risk of bias. Six models offered applications that could be readily used, but only one provided enough time to offer a planned caesarean birth (pCB). These well-refined models have not been recalibrated since development. Only one model, developed in a relatively low-risk population, with data collected a decade ago, remains useful at 36 weeks for arranging a pCB. CONCLUSION: To improve personalised clinical conversations, there is a pressing need for a model that accurately predicts the timely risk of an EmCB for women across diverse clinical backgrounds. TRIAL REGISTRATION: PROSPERO registration number: CRD42023384439.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

OBJECTIVE: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN: Superiority, double-blind randomised controlled trial. SETTING: A total of 20 UK fetal medicine units. POPULATION: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Personalized external aortic root support in aneurysm disease.

PURPOSE OF REVIEW: To bring together and annotate publications about personalised external aortic root support reported in the 18 months preceding submission. RECENT FINDINGS: The total number of personalised external aortic root support (PEARS) operations is now approaching 700 in 30 centres in Australia, Belgium, Brazil, Czech Republic, Great Britain, Greece, Ireland, Malaysia, Netherlands, New Zealand, Poland and Slovakia. There are continued reports of stability of aortic dimensions and aortic valve function with the only exceptions known being where the surgeon has deviated from the instructions for use of the device. The median root diameter of Marfan patients having PEARS was 47 mm suggesting that the existing criterion of 50 mm is due for reconsideration. The peri-operative mortality currently estimated to be less than 0.3%. The first recipient remains alive and well after 18 years. The use of PEARS as an adjunct to the Ross operation to support the pulmonary autograft is being explored in several centres. SUMMARY: The operation requires proctoring and adherence to a strict operative protocol and with those precautions excellent results are attained. The evidence and opinions provided in the cited publications indicate that PEARS is a proven and successful prophylactic operation for aortic root aneurysm.

Implementation of a novel vocal cord dysfunction management pathway using the consolidated framework for implementation research.

Every year in Australia over a thousand children who are born with congenital heart disease require surgical intervention. Vocal cord dysfunction (VCD) can be an unavoidable and potentially devastating complication of surgery for congenital heart disease. Structured, multidisciplinary care pathways help to guide clinical care and reduce mortality and morbidity. An implementation study was conducted to embed a novel, multidisciplinary management pathway into practice using the consolidated framework for implementation research (CFIR). The goal of the pathway was to prepare children with postoperative vocal cord dysfunction to safely commence and transition to oral feeding. Education sessions to support pathway rollout were completed with clinical stakeholders. Other implementation strategies used included adaptation of the pre-procedural pathway to obtain consent, improving the process of identifying patients on the VCD pathway, and nominating a small team who were responsible for the ongoing monitoring of patients following recruitment. Implementation success was evaluated according to compliance with pathway defined management. Our study found that while there were several barriers to pathway adoption, implementation of the pathway was feasible despite pathway adaptations that were required in response to COVID-19.

Glycerophospholipid and detoxification pathways associated with small for gestation age pathophysiology: discovery metabolomics analysis in the SCOPE cohort.

INTRODUCTION: Small for gestational age (SGA) may be associated with neonatal morbidity and mortality. Our understanding of the molecular pathways implicated is poor. OBJECTIVES: Our aim was to determine the metabolic pathways involved in the pathophysiology of SGA and examine their variation between maternal biofluid samples. METHODS: Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks' gestation from nulliparous low-risk pregnant women participating in the SCOPE study. Women who delivered an SGA infant (birthweight < 10th percentile) were matched to controls (uncomplicated pregnancies). Metabolomics (urine) and lipidomics (plasma) analyses were performed using ultra performance liquid chromatography-mass spectrometry. Features were ranked based on FDR adjusted p-values from empirical Bayes analysis, and significant features putatively identified. RESULTS: Lipidomics plasma analysis revealed that 22 out of the 33 significantly altered lipids annotated were glycerophospholipids; all were detected in higher levels in SGA. Metabolomic analysis identified reduced expression of metabolites associated with detoxification (D-Glucuronic acid, Estriol-16-glucuronide), nutrient absorption and transport (Sulfolithocholic acid) pathways. CONCLUSIONS: This study suggests higher levels of glycerophospholipids, and lower levels of specific urine metabolites are implicated in the pathophysiology of SGA. Further research is needed to confirm these findings in independent samples.

Physiological track-and-trigger/early warning systems for use in maternity care.

BACKGROUND: A considerable challenge for maternity care providers is recognising clinical deterioration early in pregnant women. Professional bodies recommend the use of clinical assessment protocols or evaluation tools, commonly referred to as physiological track-and-trigger systems (TTS) or early warning systems (EWS), as a means of helping maternity care providers recognise actual or potential clinical deterioration early. TTS/EWS are clinician-administered (midwife, obstetrician), bedside physiological assessment protocols, charts or tools designed to record routinely assessed clinical parameters; that is, blood pressure, temperature, heart rate, urine output and mental/neurological alertness. In general, these systems involve the application of scores or alert indicators to the observed physiological parameters based on their prespecified limits of normality. The overall system score or alert limit is then used to assist the maternity care provider identify a need to escalate care. This, in turn, may allow for earlier intervention(s) to alter the course of the emerging critical illness and ultimately reduce or avoid mortality and morbidity sequelae. OBJECTIVES: To evaluate the clinical- and cost-effectiveness of maternal physiological TTS/EWS on pregnancy, labour and birth, postpartum (up to 42 days) and neonatal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (28 May 2021), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 June 2021), OpenGrey, the ProQuest Dissertations and Theses database (7 June 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs), including cluster-RCTs, comparing physiological TTS/EWS with no system or another system. Participants were women who were pregnant or had given birth within the previous 42 days, at high risk and low risk for pregnancy, labour and birth, and postpartum complications. DATA COLLECTION AND ANALYSIS: Two review authors (VS and MN) independently assessed all identified papers for inclusion and performed risk of bias assessments. Any discrepancies were resolved through discussion and consensus. Data extraction was also conducted independently by two review authors (VS and MN) and checked for accuracy. We used the summary odds ratio (OR) with 95% confidence intervals (CIs) to present the results for dichotomous data and the mean difference (MD) with 95% CI to present the results for continuous data. MAIN RESULTS: We included two studies, a parallel RCT involving 700 women and a stepped-wedge cluster trial involving 536,233 women. Both studies were published in 2019, and both were conducted in low-resource settings. The interventions were the 'Saving Mothers Score' (SMS) and the CRADLE Vital Sign Alert (VSA) device, and both interventions were compared with standard care. Both studies had low or unclear risk of bias on all seven risk of bias criteria. Evidence certainty, assessed using GRADE, ranged from very low to moderate certainty, mainly due to other bias as well as inconsistency and imprecision. For women randomised to TTS/EWS compared to standard care there is probably little to no difference in maternal death (OR 0.80, 95% CI 0.30 to 2.11; 1 study, 536,233 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce total haemorrhage (OR 0.36, 95% CI 0.19 to 0.69; 1 study, 700 participants; low-certainty evidence). For women randomised to TTS/EWS compared to standard care there may be little to no difference in sepsis (OR 0.21, 95% CI 0.02 to 1.80; 1 study, 700 participants; low-certainty evidence), eclampsia (OR 1.50, 95% CI 0.74 to 3.03; 2 studies, 536,933 participants; low-certainty evidence) and HELLP (OR 0.21, 95% CI 0.01 to 4.40; 1 study, 700 participants; very low-certainty evidence), and probably little to no difference in maternal admission to the intensive care unit (ICU) (OR 0.78, 95% CI  0.53 to 1.15; 2 studies, 536,933 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce a woman's length of hospital stay (MD -1.21, 95% CI -1.78 to -0.64; 1 study, 700 participants; low-certainty evidence) but may result in little to no difference in neonatal death (OR 1.06, 95% CI 0.62 to 1.84; 1 study, 700 participants; low-certainty evidence). Cost-effectiveness measures were not measured in either of the two studies.  AUTHORS' CONCLUSIONS: Use of TTS/EWS in maternity care may be helpful in reducing some maternal outcomes such as haemorrhage and maternal length of hospital stay, possibly through early identification of clinical deterioration and escalation of care. The evidence suggests that the use of TTS/EWS compared to standard care probably results in little to no difference in maternal death and may result in little to no difference in neonatal death. Both of the included studies were conducted in low-resource settings where the use of TTS/EWS might potentially confer a different effect to TTS/EWS use in high-resource settings. Further high-quality trials in high- and middle-resource settings, as well as in discrete populations of high- and low-risk women, are required.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Association between phospholipid metabolism in plasma and spontaneous preterm birth: a discovery lipidomic analysis in the cork pregnancy cohort.

INTRODUCTION: Preterm birth (PTB) is defined as birth occurring before 37 weeks' gestation, affects 5-9% of all pregnancies in developed countries, and is the leading cause of perinatal mortality. Spontaneous preterm birth (sPTB) accounts for 31-50% of all PTB, but the underlying pathophysiology is poorly understood. OBJECTIVE: This study aimed to decipher the lipidomics pathways involved in pathophysiology of sPTB. METHODS: Blood samples were taken from SCreening fOr Pregnancy Endpoints (SCOPE), an international study that recruited 5628 nulliparous women, with a singleton low-risk pregnancy. Our analysis focused on plasma from SCOPE in Cork. Discovery profiling of the samples was undertaken using liquid chromatography-mass spectrometry Lipidomics, and features significantly altered between sPTB (n = 16) and Control (n = 32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons. RESULTS: Twenty-six lipids showed lower levels in plasma of sPTB compared to controls (adjusted p < 0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls. CONCLUSIONS: We report reduced levels of plasma phospholipids in sPTB. Phospholipid integrity is linked to biological membrane stability and inflammation, while storage and breakdown of lipids have previously been implicated in pregnancy complications. The contribution of phospholipids to sPTB as a cause or effect is still unclear; however, our results of differential plasma phospholipid expression represent another step in advancing our understanding of the aetiology of sPTB. Further work is needed to validate these findings in independent pregnancy cohorts.