Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth.

BACKGROUND: The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. METHODS: In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. RESULTS: A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. CONCLUSIONS: Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

Evidence for 28 genetic disorders discovered by combining healthcare and research data.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

Term planned delivery based on fetal growth assessment with or without the cerebroplacental ratio in low-risk pregnancies (RATIO37): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: The cerebroplacental ratio is associated with perinatal mortality and morbidity, but it is unknown whether routine measurement improves pregnancy outcomes. We aimed to evaluate whether the addition of cerebroplacental ratio measurement to the standard ultrasound growth assessment near term reduces perinatal mortality and severe neonatal morbidity, compared with growth assessment alone. METHODS: RATIO37 was a randomised, open-label, multicentre, pragmatic trial, conducted in low-risk pregnant women, recruited from nine hospitals over six countries. The eligibility criteria were designed to be broad; participants were required to be 18 years or older, with an ultrasound-dated confirmed singleton pregnancy in the first trimester, an alive fetus with no congenital malformations at the routine second-trimester ultrasound, an absence of adverse medical or obstetric history, and the capacity to give informed consent. Women were randomly assigned in a 1:1 ratio (block size 100) using a web-based system to either the concealed group or revealed group. In the revealed group, the cerebroplacental ratio value was known by clinicians, and if below the fifth centile, a planned delivery after 37 weeks was recommended. In the concealed group, women and clinicians were blinded to the cerebroplacental ratio value. All participants underwent ultrasound at 36 + 0 to 37 + 6 weeks of gestation with growth assessment and Doppler evaluation. In both groups, planned delivery was recommended when the estimated fetal weight was below the tenth centile. The primary outcome was perinatal mortality from 24 weeks' gestation to infant discharge. The study is registered at ClinicalTrials.gov (NCT02907242) and is now closed. FINDINGS: Between July 29, 2016, and Aug 3, 2021, we enrolled 11 214 women, of whom 9492 (84·6%) completed the trial and were eligible for analysis (4774 in the concealed group and 4718 in the revealed group). Perinatal mortality occurred in 13 (0·3%) of 4774 pregnancies in the concealed group and 13 (0·3%) of 4718 in the revealed group (OR 1·45 [95% CI 0·76-2·76]; p=0·262). Overall, severe neonatal morbidity occurred in 35 (0·73%) newborns in the concealed group and 18 (0·38%) in the revealed group (OR 0·58 [95% CI 0·40-0·83]; p=0·003). Severe neurological morbidity occurred in 13 (0·27%) newborns in the concealed group and nine (0·19%) in the revealed group (OR 0·56 [95% CI 0·25-1·24]; p=0·153). Severe non-neurological morbidity occurred in 23 (0·48%) newborns in the concealed group and nine (0·19%) in the revealed group (0·58 [95% CI 0·39-0·87]; p=0·009). Maternal adverse events were not collected. INTERPRETATION: Planned delivery at term based on ultrasound fetal growth assessment and cerebroplacental ratio at term was not followed by a reduction of perinatal mortality although significantly reduced severe neonatal morbidity compared with fetal growth assessment alone. FUNDING: La Caixa foundation, Cerebra Foundation for the Brain Injured Child, Agència per la Gestió d'Ajuts Universitaris i de Recerca, and Instituto de Salud Carlos III.

Evidence-based antenatal interventions to reduce the incidence of small vulnerable newborns and their associated poor outcomes.

A package of care for all pregnant women within eight scheduled antenatal care contacts is recommended by WHO. Some interventions for reducing and managing the outcomes for small vulnerable newborns (SVNs) exist within the WHO package and need to be more fully implemented, but additional effective measures are needed. We summarise evidence-based antenatal and intrapartum interventions (up to and including clamping the umbilical cord) to prevent vulnerable births or improve outcomes, informed by systematic reviews. We estimate, using the Lives Saved Tool, that eight proven preventive interventions (multiple micronutrient supplementation, balanced protein and energy supplementation, low-dose aspirin, progesterone provided vaginally, education for smoking cessation, malaria prevention, treatment of asymptomatic bacteriuria, and treatment of syphilis), if fully implemented in 81 low-income and middle-income countries, could prevent 5·202 million SVN births (sensitivity bounds 2·398-7·903) and 0·566 million stillbirths (0·208-0·754) per year. These interventions, along with two that can reduce the complications of preterm (<37 weeks' gestation) births (antenatal corticosteroids and delayed cord clamping), could avert 0·476 million neonatal deaths (0·181-0·676) per year. If further research substantiates the preventive effect of three additional interventions (supplementation with omega-3 fatty acids, calcium, and zinc) on SVN births, about 8·369 million SVN births (2·398-13·857) and 0·652 million neonatal deaths (0·181-0·917) could be avoided per year. Scaling up the eight proven interventions and two intrapartum interventions would cost about US$1·1 billion in 2030 and the potential interventions would cost an additional $3·0 billion. Implementation of antenatal care recommendations is urgent and should include all interventions that have proven effects on SVN babies, within the context of access to family planning services and addressing social determinants of health. Attaining high effective coverage with these interventions will be necessary to achieve global targets for the reduction of low birthweight births and neonatal mortality, and long-term benefits on growth and human capital.

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. FINDINGS: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. INTERPRETATION: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. FUNDING: UK Medical Research Council and Indian Department of Biotechnology.

Neuron-specific loss of Ppp6c induces neonatal death and decreases the number of cortical neurons and interneurons.

Protein phosphatase 6 (PP6) is a Ser/Thr protein phosphatase with the catalytic subunit Ppp6c. Recent cell-level studies have revealed that Ppp6c knockdown suppresses neurite outgrowth, suggesting that Ppp6c is involved in the development of the nervous system. We found that the function of PP6 in neurons is essential for mouse survival after birth, as all neural-stem-cell-specific KO (Ppp6cNKO) and neuron-specific KO mice died within 2 days of birth. By contrast, approximately 40 % of oligodendrocyte-specific KO mice died within 2 days of birth, whereas others survived until weaning or later, suggesting that the lethality of PP6 loss differs between neurons and oligodendrocytes. Furthermore, the fetal brain of Ppp6cNKO mice exhibited decreased numbers of neurons in layers V-VI and interneurons in layer I of the neocortex. These results suggest for the first time that Ppp6c is essential for neonatal survival and proper development of neurons and interneurons in the neocortex.

A systematic review to assess the utility of genomic autopsy using exome or genome sequencing in cases of congenital anomalies and perinatal death.

PURPOSE: Exome or genome sequencing (ES or GS) can identify genetic causes of otherwise unexplained congenital anomaly and perinatal death (PND) but is not routine practice. The evidence base for "genomic autopsy" after termination of pregnancy for fetal anomaly (TOPFA) and PND has been synthesized to determine the value of this investigation. METHODS: We conducted a systematic review and meta-analysis of studies meeting prespecified inclusion criteria and containing ≥10 cases of TOPFA or PND (with or without major congenital abnormality), in which ES or GS was conducted. We determined test performance, including diagnostic yield, accuracy, and reliability. We also reported outcomes associated with clinical utility and harms, where described. RESULTS: From 2245 potentially eligible studies, 32 publications were eligible and had data extracted, representing 2120 cases that could be meta-analyzed. No diagnostic accuracy or comparative studies were identified, although some analysis of concordance between different ES/GS methodologies could be performed. Studies reporting parent-related outcomes or long-term follow-up did not do so in a systematic or quantifiable manner. CONCLUSION: Evidence suggests that approximately one-fourth to one-third of fetal losses associated with TOPFA or unexplained PND are associated with a genetic cause identifiable on ES or GS-albeit this estimate varies depending on phenotypic and background risk factors. Despite the large body of evidence on ES and GS, little research has attempted to validate the accuracy of testing, nor measure the clinical or societal outcomes in families that follow the diagnostic investigation in this context.

Desirability of outcome ranking for obstetrical trials: illustration and application to the ARRIVE trial.

BACKGROUND: In randomized trials, 1 primary outcome is typically chosen to evaluate the consequences of an intervention, whereas other important outcomes are relegated to secondary outcomes. This issue is amplified for many obstetrical trials in which an intervention may have consequences for both the pregnant person and the child. In contrast, desirability of outcome ranking, a paradigm shift for the design and analysis of clinical trials based on patient-centric evaluation, allows multiple outcomes-including from >1 individual-to be considered concurrently. OBJECTIVE: This study aimed to describe desirability of outcome ranking methodology tailored to obstetrical trials and to apply the methodology to maternal-perinatal paired (dyadic) outcomes in which both individuals may be affected by an intervention but may experience discordant outcomes (eg, an obstetrical intervention may improve perinatal but worsen maternal outcomes). STUDY DESIGN: This secondary analysis applies the desirability of outcome ranking methodology to data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network ARRIVE trial. The original analysis found no substantial difference in the primary (perinatal composite) outcome, but a decreased risk of the secondary outcome of cesarean delivery with elective induction at 39 weeks. In the present desirability-of-outcome-ranking analysis, dyadic outcomes ranging from spontaneous vaginal delivery without severe neonatal complication (most desirable) to cesarean delivery with perinatal death (least desirable) were classified into 8 categories ranked by overall desirability by experienced investigators. Distributions of the desirability of outcome ranking were compared by estimating the probability of having a more desirable dyadic outcome with elective induction at 39 weeks of gestation than with expectant management. To account for various perspectives on these outcomes, a complementary analysis, called the partial credit strategy, was used to grade outcomes on a 100-point scale and estimate the difference in overall treatment scores between groups using a t test. RESULTS: All 6096 participants from the trial were included. The probability of a better dyadic outcome for a randomly selected patient who was randomized to elective induction was 53% (95% confidence interval, 51-54), implying that elective induction led to a better overall outcome for the dyad when taking multiple outcomes into account concurrently. Furthermore, the desirability-of-outcome-ranking probability of averting cesarean delivery with elective induction was 52% (95% confidence interval, 51-53), which was not at the expense of an operative vaginal delivery or a poorer outcome for the perinate (ie, survival with a severe neonatal complication or perinatal death). Randomization to elective induction was also advantageous in most of the partial credit score scenarios. CONCLUSION: Desirability-of-outcome-ranking methodology is a useful tool for obstetrical trials because it provides a concurrent view of the effect of an intervention on multiple dyadic outcomes, potentially allowing for better translation of data for decision-making and person-centered care.

Intrapartum cardiotocography with simultaneous maternal heart rate registration improves neonatal outcome.

BACKGROUND: Intrapartum cardiotocographic monitoring of fetal heart rate by abdominal external ultrasound transducer without simultaneous maternal heart rate recording has been associated with increased risk of early neonatal death and other asphyxia-related neonatal outcomes. It is unclear, however, whether this increase in risk is independently associated with fetal surveillance method or is attributable to other factors. OBJECTIVE: This study aimed to compare different fetal surveillance methods and their association with adverse short- and long-term fetal and neonatal outcomes in a large retrospective cohort of spontaneous term deliveries. STUDY DESIGN: Fetal heart rate and maternal heart rate patterns were recorded by cardiotocography during labor in spontaneous term singleton cephalic vaginal deliveries in the Hospital District of Helsinki and Uusimaa, Finland between October 1, 2005, and September 30, 2023. According to the method of cardiotocography monitoring at birth, the cohort was divided into the following 3 groups: women with ultrasound transducer, women with both ultrasound transducer and maternal heart rate transducer, and women with internal fetal scalp electrode. Umbilical artery pH and base excess values, low 1- and 5-minute Apgar scores, need for intubation and resuscitation, neonatal intensive care unit admission for asphyxia, neonatal encephalopathy, and early neonatal death were used as outcome variables. RESULTS: Among the 213,798 deliveries that met the inclusion criteria, the monitoring type was external ultrasound transducer in 81,559 (38.1%), both external ultrasound transducer and maternal heart rate recording in 62,268 (29.1%), and fetal scalp electrode in 69,971 (32.7%) cases, respectively. The rates of both neonatal encephalopathy (odds ratio, 1.48; 95% confidence interval, 1.08-2.02) and severe acidemia (umbilical artery pH <7.00 and/or umbilical artery base excess ≤-12.0 mmol/L) (odds ratio, 2.03; 95% confidence interval, 1.65-2.50) were higher in fetuses of women with ultrasound transducer alone compared with those of women with concurrent external fetal and maternal heart rate recording. Monitoring with ultrasound transducer alone was also associated with increased risk of neonatal intubation for resuscitation (odds ratio, 1.22; 95% confidence interval, 1.03-1.44). A greater risk of severe neonatal acidemia was observed both in the ultrasound transducer (odds ratio, 2.78; 95% confidence interval, 2.23-3.48) and concurrent ultrasound transducer and maternal heart rate recording (odds ratio, 1.37; 95% confidence interval, 1.05-1.78) groups compared with those monitored with fetal scalp electrodes. No difference in risk of neonatal encephalopathy was found between newborns monitored with concurrent ultrasound transducer and maternal heart rate recording and those monitored with fetal scalp electrodes. CONCLUSION: The use of external ultrasound transducer monitoring of fetal heart rate without simultaneous maternal heart rate recording is associated with higher rates of neonatal encephalopathy and severe neonatal acidemia. We suggest that either external fetal heart rate monitoring with concurrent maternal heart rate recording or internal fetal scalp electrode be used routinely as a fetal surveillance tool in term deliveries.

Gestational diabetes mellitus and adverse maternal and perinatal outcomes in twin and singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). DATA SOURCES: A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May 2023. STUDY ELIGIBILITY CRITERIA: Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. METHODS: This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. RESULTS: Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. CONCLUSION: In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

Incidence and causes of perinatal death in prenatally diagnosed vasa previa: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to estimate the perinatal mortality associated with prenatally diagnosed vasa previa and to determine what proportion of those perinatal deaths are directly attributable to vasa previa. DATA SOURCES: The following databases have been searched from January 1, 1987, to January 1, 2023: PubMed, Scopus, Web of Science, and Embase. STUDY ELIGIBILITY CRITERIA: Our study included all studies (cohort studies and case series or reports) that had patients in which a prenatal diagnosis of vasa previa was made. Case series or reports were excluded from the meta-analysis. All cases in which prenatal diagnosis was not made were excluded from the study. METHODS: The programming language software R (version 4.2.2) was used to conduct the meta-analysis. The data were logit transformed and pooled using the fixed effects model. The between-study heterogeneity was reported by I2. The publication bias was evaluated using a funnel plot and the Peters regression test. The Newcastle-Ottawa scale was used to assess the risk of bias. RESULTS: Overall, 113 studies with a cumulative sample size of 1297 pregnant individuals were included. This study included 25 cohort studies with 1167 pregnancies and 88 case series or reports with 130 pregnancies. Moreover, 13 perinatal deaths occurred among these pregnancies, consisting of 2 stillbirths and 11 neonatal deaths. Among the cohort studies, the overall perinatal mortality was 0.94% (95% confidence interval, 0.52-1.70; I2=0.0%). The pooled perinatal mortality attributed to vasa previa was 0.51% (95% confidence interval, 0.23-1.14; I2=0.0%). Stillbirth and neonatal death were reported in 0.20% (95% confidence interval, 0.05-0.80; I2=0.0%) and 0.77% (95% confidence interval, 0.40-1.48; I2=0.0%) of pregnancies, respectively. CONCLUSION: Perinatal death is uncommon after a prenatal diagnosis of vasa previa. Approximately half of the cases of perinatal mortality are not directly attributable to vasa previa. This information will help in guiding physicians in counseling and will provide reassurance to pregnant individuals with a prenatal diagnosis of vasa previa.

Birth and postnatal outcomes among infants of immigrant parents of different admission categories and parents born in Canada: a population-based retrospective study.

BACKGROUND: Most studies of disparities in birth and postnatal outcomes by parental birthplace combine all immigrants into a single group. We sought to evaluate heterogeneity among immigrants in Canada by comparing birth and postnatal outcomes across different immigration categories. METHODS: We conducted a population-based retrospective study using Statistics Canada data on live births and stillbirths (1993-2017) and infant deaths (1993-2018), linked to parental immigration data (1960-2017). We classified birthing parents as born in Canada, economic-class immigrants, family-class immigrants, or refugees, and evaluated differences in preterm births, small-for-gestational-age (SGA) and large-for-gestational-age (LGA) births, stillbirths, and infant deaths among singleton births by group. RESULTS: Among 7 980 650 births, 1 715 050 (21.5%) were to immigrants, including 632 760 (36.9%) in the economic class, 853 540 (49.8%) in the family class, and 228 740 (13.4%) refugees. Compared with infants of Canadian-born birthing parents, infants of each of the 3 immigrant groups had higher risk of preterm birth, SGA birth, and stillbirth, but lower risk of LGA birth and neonatal death. Compared with infants of economic-class immigrants, infants of refugees had higher risk of early preterm birth (0.9% v. 0.8%, adjusted risk ratio [RR] 1.08, 95% confidence interval [CI] 1.01-1.15) and LGA birth (9.2% v. 7.5%, adjusted RR 1.12, 95% CI 1.10-1.15), but lower risk of SGA birth (10.2% v. 11.0%, adjusted RR 0.92, 95% CI 0.90-0.94), while infants of family-class immigrants had higher risk of SGA birth (12.2% v. 11.0%, adjusted RR 1.01, 95% CI 1.00-1.02). Risk of stillbirth, neonatal death, and overall infant death did not differ significantly among immigrant groups. INTERPRETATION: Heterogeneity exists in outcomes of infants born to immigrants to Canada across immigration categories. These results highlight the importance of disaggregating immigrant populations in studies of health disparities.

Global prevalence and burden of multidrug-resistant tuberculosis from 1990 to 2019.

BACKGROUND: Tuberculosis(TB) remains a pressing public health challenge, with multidrug-resistant tuberculosis (MDR-TB) emerging as a major threat. And healthcare authorities require reliable epidemiological evidence as a crucial reference to address this issue effectively. The aim was to offer a comprehensive epidemiological assessment of the global prevalence and burden of MDR-TB from 1990 to 2019. METHODS: Estimates and 95% uncertainty intervals (UIs) for the age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized disability-adjusted life years rate (ASR of DALYs), and age-standardized death rate (ASDR) of MDR-TB were obtained from the Global Burden of Disease (GBD) 2019 database. The prevalence and burden of MDR-TB in 2019 were illustrated in the population and regional distribution. Temporal trends were analyzed by using Joinpoint regression analysis to calculate the annual percentage change (APC), average annual percentage change (AAPC) and its 95% confidence interval(CI). RESULTS: The estimates of the number of cases were 687,839(95% UIs: 365,512 to 1223,262), the ASPR were 8.26 per 100,000 (95%UIs: 4.61 to 15.20), the ASR of DALYs were 52.38 per 100,000 (95%UIs: 22.64 to 97.60) and the ASDR were 1.36 per 100,000 (95%UIs: 0.54 to 2.59) of MDR-TB at global in 2019. Substantial burden was observed in Africa and Southeast Asia. Males exhibited higher ASPR, ASR of DALYs, and ASDR than females across most age groups, with the burden of MDR-TB increasing with age. Additionally, significant increases were observed globally in the ASIR (AAPC = 5.8; 95%CI: 5.4 to 6.1; P < 0.001), ASPR (AAPC = 5.9; 95%CI: 5.4 to 6.4; P < 0.001), ASR of DALYs (AAPC = 4.6; 95%CI: 4.2 to 5.0; P < 0.001) and ASDR (AAPC = 4.4; 95%CI: 4.0 to 4.8; P < 0.001) of MDR-TB from 1990 to 2019. CONCLUSIONS: This study underscored the persistent threat of drug-resistant tuberculosis to public health. It is imperative that countries and organizations worldwide take immediate and concerted action to implement measures aimed at significantly reducing the burden of TB.

Determinants of stillbirths in sub-Saharan Africa: A systematic review.

BACKGROUND: Sub-Saharan African (SSA) countries have high stillbirth rates compared with high-income countries, yet research on risk factors for stillbirth in SSA remain scant. OBJECTIVES: To identify the modifiable risk factors of stillbirths in SSA and investigate their strength of association using a systematic review. SEARCH STRATEGY: CINAHL Plus, EMBASE, Global Health and MEDLINE databases were searched for literature. SELECTION CRITERIA: Observational population- and facility-level studies exploring stillbirth risk factors, published in 2013-2019 were included. DATA COLLECTION AND ANALYSIS: A narrative synthesis of data was undertaken and the potential risk factors were classified into subgroups. MAIN RESULTS: Thirty-seven studies were included, encompassing 20 264 stillbirths. The risk factors were categorised as: maternal antepartum factors (0-4 antenatal care visits, multiple gestations, hypertension, birth interval of >3 years, history of perinatal death); socio-economic factors (maternal lower wealth index and basic education, advanced maternal age, grand multiparity of ≥5); intrapartum factors (direct obstetric complication); fetal factors (low birthweight and gestational age of <37 weeks) and health systems factors (poor quality of antenatal care, emergency referrals, ill-equipped facility). The proportion of unexplained stillbirths remained very high. No association was found between stillbirths and body mass index, diabetes, distance from the facility or HIV. CONCLUSIONS: The overall quality of evidence was low, as many studies were facility based and did not adjust for confounding factors. This review identified preventable risk factors for stillbirth. Focused programmatic strategies to improve antenatal care, emergency obstetric care, maternal perinatal education, referral and outreach systems, and birth attendant training should be developed. More population-based, high-quality research is needed.

Selective fetal growth restriction in dichorionic diamniotic twin pregnancy: systematic review and meta-analysis of pregnancy and perinatal outcomes.

OBJECTIVE: Most of the published literature on selective fetal growth restriction (sFGR) has focused on monochorionic twin pregnancies. The aim of this systematic review was to report on the outcome of dichorionic diamniotic (DCDA) twin pregnancies complicated by sFGR. METHODS: MEDLINE, EMBASE and The Cochrane Library databases were searched. The inclusion criteria were DCDA twin pregnancies complicated by sFGR. The outcomes explored were intrauterine death (IUD), neonatal death and perinatal death (PND), survival of at least one and both twins, preterm birth (PTB) (either spontaneous or iatrogenic) prior to 37, 34, 32 and 28 weeks' gestation, pre-eclampsia (PE) or gestational hypertension, neurological, respiratory and infectious morbidity, Apgar score < 7 at 5 min, necrotizing enterocolitis, retinopathy of prematurity and admission to the neonatal intensive care unit (NICU). A composite outcome of neonatal morbidity, defined as the occurrence of respiratory, neurological or infectious morbidity, was also evaluated. Random-effects meta-analysis was used to analyze the data, and results are reported as pooled proportion or odds ratio (OR) with 95% CI. RESULTS: Thirteen studies reporting on 1339 pregnancies with sFGR and 6316 pregnancies without sFGR were included. IUD occurred in 2.6% (95% CI, 1.1-4.7%) of fetuses from DCDA pregnancies with sFGR and 0.6% (95% CI, 0.3-9.7%) of those from DCDA pregnancies without sFGR, while the respective values for PND were 5.2% (95% CI, 3.5-7.3%) and 1.7% (95% CI, 0.1-5.7%). Spontaneous or iatrogenic PTB before 37 weeks complicated 84.1% (95% CI, 55.6-99.2%) of pregnancies with sFGR and 69.1% (95% CI, 45.4-88.4%) of those without sFGR. The respective values for PTB before 34, 32 and 28 weeks were 18.4% (95% CI, 4.4-38.9%), 13.0% (95% CI, 9.5-17.1%) and 1.5% (95% CI, 0.6-2.3%) in pregnancies with sFGR and 10.2% (95% CI, 3.1-20.7%), 7.8% (95% CI, 6.8-9.0%) and 1.8% (95% CI, 1.3-2.4%) in those without sFGR. PE or gestational hypertension complicated 19.9% (95% CI, 12.4-28.6%) of pregnancies with sFGR and 12.8% (95% CI, 10.4-15.4%) of those without sFGR. Composite morbidity occurred in 28.2% (95% CI, 7.8-55.1%) of fetuses from pregnancies with sFGR and 13.9% (95% CI, 6.5-23.5%) of those from pregnancies without sFGR. When stratified according to the sFGR status within a twin pair, composite morbidity occurred in 39.0% (95% CI, 11.1-71.5%) of growth-restricted fetuses and 29.9% (95% CI, 3.5-65.0%) of appropriately grown fetuses (OR, 1.9 (95% CI, 1.7-3.1)), while the respective values for PND were 3.0% (95% CI, 1.8-4.5%) and 1.6% (95% CI, 0.9-2.6%) (OR, 2.1 (95% CI, 1.0-4.1)). On risk analysis, DCDA pregnancies complicated by sFGR had a significantly higher risk of IUD (OR, 5.2 (95% CI, 3.2-8.6)) and composite morbidity or admission to the NICU (OR, 3.2 (95% CI, 1.9-5.6)) compared to those without sFGR, while there was no difference in the risk of PTB before 34 weeks (P = 0.220) or PE/gestational hypertension (P = 0.210). CONCLUSIONS: DCDA twin pregnancies complicated by sFGR are at high risk of perinatal morbidity and mortality. The findings of this systematic review are relevant for counseling and management of complicated DCDA twin pregnancies, in which twin-specific, rather than singleton, outcome data should be used. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The incidence of retinopathy of prematurity in neonates in Germany in 2019; a nationwide epidemiological cohort study.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness in preterm infants. The incidence of ROP varies widely across countries, with rates as high as 30% in some regions. This study investigated the incidence, risk factors, treatment, and mortality of ROP patients in Germany. Data were extracted from the German Federal Statistical Office (Destatis) diagnosis-related group (DRG) and Institute for the Remuneration System in Hospitals (InEK) databases. Patients with a secondary diagnosis of ROP (ICD-10 code H35.1) in the first 28 days of life were included. Data were extracted for patients admitted between January 1, 2019 and December 31, 2019. The diagnoses and procedures were determined using the German version of the International Classification of Diseases (ICD-10-GM) and the German procedure coding system (OPS). The codes 5-154.xx, 5-155.xx, 8-020.xx, 5-156.9, 6-003.(c&d), 6-007.(2&8) were utilised to denote different ocular treatments. Patient Clinical Complexity Levels were extracted and used to compare ROP with non-ROP patients. A total of 1326 patients with ROP were identified. The incidence of ROP is estimated to be 17.04 per 10,000 live births. The incidence was highest in infants with birth weights less than 500 g and decreased with increasing birth weight. The most common risk factors for ROP were low birth weight, male sex, and prematurity. Of the infants with ROP, 7.2% required ocular treatment. The most common treatment was intraocular injections, followed by photocoagulation. No surgical treatment was required for any of the infants during the study period. The mortality rate for infants with ROP was 60.33 per 10,000. This is higher than the overall neonatal death rate of 24.2 per 10,000. CONCLUSIONS: This study found that the incidence of ROP in Germany is similar to that in other developed countries. The study also found that the mortality rate for infants with ROP is higher than the overall neonatal death rate. These findings highlight the importance of early detection and treatment of ROP in preterm infants. WHAT IS KNOWN: • ROP is a severe eye condition often affecting preterm infants. • Previous data are limited in scope and generalizability. WHAT IS NEW: • Based on a national database, our study found ROP incidence to be 17.04 per 10,000 new births, higher in males (17.71) than in females (16.34). • 7.2% of ROP cases required ocular treatment, inversely correlated with birth weight. • High rates of multimorbidity such as neonatal jaundice (84.69%), respiratory distress syndrome (80.84%), and apnea (78.88%) were observed.

Outcomes of fetal lower urinary tract obstruction based on timing of oligohydramnios onset.

OBJECTIVE: Fetal Lower Urinary Tract Obstruction (LUTO) is associated with oligohydramnios and significant fetal morbidity, resulting in poor lung development and perinatal death. However, oligohydramnios may develop at different gestational periods, and the impact of timing on fetal outcomes remains unknown. Our objective was to characterize the impact onset of oligohydramnios had on prenatal outcomes. METHODS: This study is a retrospective cohort study of all patients with a prenatal diagnosis of LUTO at our tertiary referral center from 2014 to 2023. All patients underwent detailed ultrasonography and interdisciplinary counseling and were subsequently delivered at our institution. Data were obtained from electronic medical records and complete extraction was required for final inclusion. RESULTS: During the study time period, 93 patients met inclusion criteria of which 68 (73.1%) developed oligohydramnios during their pregnancy. 63 (93%) of these pregnancies resulted in livebirths with 28 (41.1%) perinatal deaths. Onset of oligohydramnios was earlier in pregnancies with perinatal death (23 vs. 28 weeks, p = 0.004) and associated with pulmonary hypoplasia. CONCLUSIONS: Our data show the impact of oligohydramnios timing in pregnancy on pulmonary hypoplasia and ultimately perinatal death. This allows for detailed patient counseling on the impact oligohydramnios may have on pregnancies by the gestational age of onset.

Predictors of fetal death, neonatal survival and neurological outcomes in severe twin-twin transfusion syndrome treated by laser ablation of placental vessels.

OBJECTIVES: To identify predictors of outcomes in severe twin oligo-polyhydramnios sequence (TOPS) with or without twin anemia-polycythemia sequence (TAPS) and/or selective fetal growth restriction (SFGR) treated by laser ablation of placental vessels (LAPV). METHODS: Analysis of cases treated from 2011 to 2022. Variables evaluated Prenatal predictors: stages of TOPS, presence of TAPS and/or SFGR; pre-LAPV fetal ultrasound parameters; peri-LAPV variables. Perinatal predictors: GA at birth; birthweight; Apgar scores; transfontanellar ultrasonography (TFUS). OUTCOME VARIABLES: fetal death, neonatal survival, infant's neurodevelopment. Binary logistic regression analyses were performed to detect predictors of outcomes. RESULTS: 265 cases were included. Predictors of post-LAPV donor fetus' death were delta EFW (p:0.045) and absent/reverse end-diastolic flow in the umbilical artery (AREDF-UA) (p < 0.001). The predictor of post-LAPV recipient fetus' death was hydrops (p:0.009). Predictors of neonatal survival were GA at birth and Apgar scores. Predictors of infant's neurodevelopment were TFUS and pre-LAPV middle cerebral artery Doppler (MCAD) for the donor twin; and pre-LAPV ductus venosus' flow and MCAD for the recipient twin. CONCLUSIONS: Prediction of fetal death, neonatal survival and infant's neurodevelopment is possible in cases of TOPS associated or not with SFGR and/or TAPS that were treated by LAPV.

Midwife continuity of care models versus other models of care for childbearing women.

BACKGROUND: Midwives are primary providers of care for childbearing women globally and there is a need to establish whether there are differences in effectiveness between midwife continuity of care models and other models of care. This is an update of a review published in 2016. OBJECTIVES: To compare the effects of midwife continuity of care models with other models of care for childbearing women and their infants. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) (17 August 2022), as well as the reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished trials in which pregnant women are randomly allocated to midwife continuity of care models or other models of care during pregnancy and birth. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion criteria, scientific integrity, and risk of bias, and carried out data extraction and entry. Primary outcomes were spontaneous vaginal birth, caesarean section, regional anaesthesia, intact perineum, fetal loss after 24 weeks gestation, preterm birth, and neonatal death. We used GRADE to rate the certainty of evidence. MAIN RESULTS: We included 17 studies involving 18,533 randomised women. We assessed all studies as being at low risk of scientific integrity/trustworthiness concerns. Studies were conducted in Australia, Canada, China, Ireland, and the United Kingdom. The majority of the included studies did not include women at high risk of complications. There are three ongoing studies targeting disadvantaged women. Primary outcomes Based on control group risks observed in the studies, midwife continuity of care models, as compared to other models of care, likely increase spontaneous vaginal birth from 66% to 70% (risk ratio (RR) 1.05, 95% confidence interval (CI) 1.03 to 1.07; 15 studies, 17,864 participants; moderate-certainty evidence), likelyreduce caesarean sections from 16% to 15% (RR 0.91, 95% CI 0.84 to 0.99; 16 studies, 18,037 participants; moderate-certainty evidence), and likely result in little to no difference in intact perineum (29% in other care models and 31% in midwife continuity of care models, average RR 1.05, 95% CI 0.98 to 1.12; 12 studies, 14,268 participants; moderate-certainty evidence). There may belittle or no difference in preterm birth (< 37 weeks) (6% under both care models, average RR 0.95, 95% CI 0.78 to 1.16; 10 studies, 13,850 participants; low-certainty evidence). We arevery uncertain about the effect of midwife continuity of care models on regional analgesia (average RR 0.85, 95% CI 0.79 to 0.92; 15 studies, 17,754 participants, very low-certainty evidence), fetal loss at or after 24 weeks gestation (average RR 1.24, 95% CI 0.73 to 2.13; 12 studies, 16,122 participants; very low-certainty evidence), and neonatal death (average RR 0.85, 95% CI 0.43 to 1.71; 10 studies, 14,718 participants; very low-certainty evidence). Secondary outcomes When compared to other models of care, midwife continuity of care models likely reduce instrumental vaginal birth (forceps/vacuum) from 14% to 13% (average RR 0.89, 95% CI 0.83 to 0.96; 14 studies, 17,769 participants; moderate-certainty evidence), and may reduceepisiotomy 23% to 19% (average RR 0.83, 95% CI 0.77 to 0.91; 15 studies, 17,839 participants; low-certainty evidence). When compared to other models of care, midwife continuity of care models likelyresult in little to no difference inpostpartum haemorrhage (average RR 0.92, 95% CI 0.82 to 1.03; 11 studies, 14,407 participants; moderate-certainty evidence) and admission to special care nursery/neonatal intensive care unit (average RR 0.89, 95% CI 0.77 to 1.03; 13 studies, 16,260 participants; moderate-certainty evidence). There may be little or no difference in induction of labour (average RR 0.92, 95% CI 0.85 to 1.00; 14 studies, 17,666 participants; low-certainty evidence), breastfeeding initiation (average RR 1.06, 95% CI 1.00 to 1.12; 8 studies, 8575 participants; low-certainty evidence), and birth weight less than 2500 g (average RR 0.92, 95% CI 0.79 to 1.08; 9 studies, 12,420 participants; low-certainty evidence). We are very uncertain about the effect of midwife continuity of care models compared to other models of care onthird or fourth-degree tear (average RR 1.10, 95% CI 0.81 to 1.49; 7 studies, 9437 participants; very low-certainty evidence), maternal readmission within 28 days (average RR 1.52, 95% CI 0.78 to 2.96; 1 study, 1195 participants; very low-certainty evidence), attendance at birth by a known midwife (average RR 9.13, 95% CI 5.87 to 14.21; 11 studies, 9273 participants; very low-certainty evidence), Apgar score less than or equal to seven at five minutes (average RR 0.95, 95% CI 0.72 to 1.24; 13 studies, 12,806 participants; very low-certainty evidence) andfetal loss before 24 weeks gestation (average RR 0.82, 95% CI 0.67 to 1.01; 12 studies, 15,913 participants; very low-certainty evidence). No maternal deaths were reported across three studies. Although the observed risk of adverse events was similar between midwifery continuity of care models and other models, our confidence in the findings was limited. Our confidence in the findings was lowered by possible risks of bias, inconsistency, and imprecision of some estimates. There were no available data for the outcomes: maternal health status, neonatal readmission within 28 days, infant health status, and birth weight of 4000 g or more. Maternal experiences and cost implications are described narratively. Women receiving care from midwife continuity of care models, as opposed to other care models, generally reported more positive experiences during pregnancy, labour, and postpartum. Cost savings were noted in the antenatal and intrapartum periods in midwife continuity of care models. AUTHORS' CONCLUSIONS: Women receiving midwife continuity of care models were less likely to experience a caesarean section and instrumental birth, and may be less likely to experience episiotomy. They were more likely to experience spontaneous vaginal birth and report a positive experience. The certainty of some findings varies due to possible risks of bias, inconsistencies, and imprecision of some estimates. Future research should focus on the impact on women with social risk factors, and those at higher risk of complications, and implementation and scaling up of midwife continuity of care models, with emphasis on low- and middle-income countries.

Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure.

BACKGROUND: Children exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain, and teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development. STUDY DESIGN: To determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow, we performed high resolution in vivo ultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12-15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55,940 (750 µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30 min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day 16 (post-exposure). RESULTS: All drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in cannabis-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p = 0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p = 0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%). CONCLUSIONS: Fetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure.