Predicting early mortality and severe intraventricular hemorrhage in very-low birth weight preterm infants: a nationwide, multicenter study using machine learning.

Our aim was to develop a machine learning-based predictor for early mortality and severe intraventricular hemorrhage (IVH) in very-low birth weight (VLBW) preterm infants in Taiwan. We collected retrospective data from VLBW infants, dividing them into two cohorts: one for model development and internal validation (Cohort 1, 2016-2021), and another for external validation (Cohort 2, 2022). Primary outcomes included early mortality, severe IVH, and early poor outcomes (a combination of both). Data preprocessing involved 23 variables, with the top four predictors identified as gestational age, birth body weight, 5-min Apgar score, and endotracheal tube ventilation. Six machine learning algorithms were employed. Among 7471 infants analyzed, the selected predictors consistently performed well across all outcomes. Logistic regression and neural network models showed the highest predictive performance (AUC 0.81-0.90 in both internal and external validation) and were well-calibrated, confirmed by calibration plots and the lowest two mean Brier scores (0.0685 and 0.0691). We developed a robust machine learning-based outcome predictor using only four accessible variables, offering valuable prognostic information for parents and aiding healthcare providers in decision-making.

Predicting severe intraventricular hemorrhage or early death using machine learning algorithms in VLBWI of the Korean Neonatal Network Database.

Severe intraventricular hemorrhage (IVH) in premature infants can lead to serious neurological complications. This retrospective cohort study used the Korean Neonatal Network (KNN) dataset to develop prediction models for severe IVH or early death in very-low-birth-weight infants (VLBWIs) using machine-learning algorithms. The study included VLBWIs registered in the KNN database. The outcome was the diagnosis of IVH Grades 3-4 or death within one week of birth. Predictors were categorized into three groups based on their observed stage during the perinatal period. The dataset was divided into derivation and validation sets at an 8:2 ratio. Models were built using Logistic Regression with Ridge Regulation (LR), Random Forest, and eXtreme Gradient Boosting (XGB). Stage 1 models, based on predictors observed before birth, exhibited similar performance. Stage 2 models, based on predictors observed up to one hour after birth, showed improved performance in all models compared to Stage 1 models. Stage 3 models, based on predictors observed up to one week after birth, showed the best performance, particularly in the XGB model. Its integration into treatment and management protocols can potentially reduce the incidence of permanent brain injury caused by IVH during the early stages of birth.

Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants.

PURPOSE: To analyze the association between risk factors and severe intraventricular hemorrhage (grade II-IV) in PNB under 1500 g. METHODS: Multicenter, retrospective, analytical, case-control study in PNB under 34 weeks and under 1500 g admitted to the NICU. CASE: PNB with severe intraventricular hemorrhage (grade II-IV). Logistic regression analysis was used to adjust for IVH-associated variables and odds ratios (OR). RESULTS: A total of 90 PNB files were analyzed, 45 cases and 45 controls. The highest risk factors for severe IVH were lower gestational age (OR 1.3, p < 0.001), perinatal asphyxia (OR 12, p < 0.001), Apgar < 6 at minute 1 and 5 (OR 6.3, p < 0.001). CONCLUSION: Lower gestational age, birth asphyxia, Apgar score lower of 6, and respiratory-type factors are associated with increased risk for severe IVH.

The role of the brain-sparing effect of growth-restricted fetuses in newborn germinal matrix/intraventricular hemorrhage.

OBJECTIVES: The aim of the study was to evaluate the effect of the brain-sparing effect (BSE) of fetal growth restriction (FGR) in newborn germinal matrix/intraventricular hemorrhage (GM/IVH). METHODS: A total of 320 patients who delivered prior to the 34th gestational week were analyzed from data records. 201 patients were divided into two groups according to cerebro-placental ratio (CPR): early fetal growth restriction (FGR) with abnormal CPR group (n=104) and appropriate for gestational age with normal Doppler group (control) (n=97). Using the normal middle cerebral artery (MCA) Doppler as a reference, multivariate logistic regression analysis was used to assess the association between the BSE and the primary outcome. RESULTS: The rate of Grade I-II germinal matrix/intraventricular hemorrhage (GM/IVH) was 31(29.8%) in the group possessing early FGR with abnormal CPR and 7(7.2%) in the control group, showing a statistically significant difference. The rate of grade III-IV GM/IVH was 7(6.7%) in the group possessing early FGR with abnormal CPR and 2 (2.1%) in the control group, showing no statistically significant difference. We found that gestational age at delivery <32 weeks was an independent risk factor for GM/IVH. In addition, we found that other variables such as the presence of preeclampsia, fetal weight percentile <10, emergency CS delivery, 48-h completion after the first steroid administration and 24-h completion rate after MgSO4 administration were not independently associated with the primary outcome. CONCLUSIONS: Our results indicate that the rate of GM-IVH was increased in the group possessing early FGR with abnormal CPR; however, multivariate logistic regression analysis showed that BSE was not an independent risk factor for GM/IVH.

Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study.

OBJECTIVES: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS). METHODS: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit's policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications. RESULTS: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70). CONCLUSIONS: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes.

Callosal Diffusion-Restriction in Patients with Intracranial Hemorrhage.

OBJECTIVE: We aim to report the incidence and clinical characteristics of patients who were found to have diffusion restricting lesions of the corpus callosum (CC) on Diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI) following intracranial hemorrhage (ICH). DESIGN/METHODS: A retrospective cross-sectional analysis was performed of medical records of all adult patients admitted to a single tertiary center with a primary diagnosis of ICH and received nicardipine infusion over a 2-year period. Patients without MRI brain available or patients who underwent digital subtraction angiography (DSA) prior to MRI were excluded. ICH and intraventricular hemorrhage (IVH) volumes and scores were calculated. MRI brain scans were evaluated for presence and locations of DWI lesions. RESULTS: Among 162 patients who met inclusion criteria, 6 patients (4%, median age 53, range 37-71, 100% male, 33% white) were found to have DWI lesions in the CC with a median ICH volume of 17ml (range 1-105ml). The ICH locations were lobar (n=3), deep (n=2) and cerebellum (n=1). All patients (100%) had intraventricular hemorrhage (IVH) with median IVH volume of 25ml (range 2.7-55ml). Four patients were on levetiracetam. No identifiable infections or metabolic abnormalities were found among these patients. All but one patient had normal DSA. Follow up MRI was only available in one patient and showed no reversibility at 14 days. CONCLUSION: Although rare, diffusion restricting corpus callosum lesions can be seen in patients with ICH, especially in patients with IVH. The etiology and clinical significance of these lesions remains unknown and warrant further research.

Intraventricular Hemorrhage in Premature Infants: A Historical Review.

Intraventricular hemorrhage (IVH) is common in premature newborns and poses a high risk for morbidity with lifelong disability. We searched the available literature for original and secondary literature regarding the epidemiology, pathogenesis, and treatment of IVH in order to trace changes in the management of this disease over time. We examined IVH pathogenesis and epidemiology and reviewed the history of medical and surgical treatment for intraventricular hemorrhage in preterm children. Initial medical management strategies aimed at correcting coagulopathy and eventually targeted mediators of perinatal instability including respiratory distress. Surgical management centered around cerebrospinal fluid diversion, initially through serial lumbar punctures, progressing to ventriculoperitoneal shunting, with more recent interventions addressing intraventricular clot burden. We provide a historical review of the evolution of treatment for IVH in newborns. While the management of IVH has grown significantly over time, IVH remains a common neurosurgical disease that continues to affect patient and caregiver quality of life and health care costs. Despite advances in treatment over more than a century, IVH remains a significant cause of morbidity and mortality in premature infants, and an understanding of past approaches may inform the development of new treatments.

Mortality and Morbidities according to Time of Birth in Extremely Low Birth Weight Infants.

BACKGROUND: Although the overall quality of high-risk neonatal care has improved recently, there is still concern about a difference in the quality of care when comparing off-hour births and regular-hour births. Moreover, there are no data in Korea regarding the impact of time of birth on mortality and morbidities in preterm infants. METHODS: A total of 3,220 infants weighing < 1,000 g and born at 23-34 weeks in 2013-2017 were analyzed based on the Korean Neonatal Network data. Mortality and major morbidities were analyzed using logistic regression according to time of birth during off-hours (nighttime, weekend, and holiday) and regular hours. The institutes were sub-grouped into hospital group I and hospital group II based on the neonatal intensive care unit (NICU) care level defined by the mortality rates of < 50% and ≥ 50%, respectively, in infants born at 23-24 weeks' gestation. RESULTS: The number of births during regular hours and off-hours was similar. In the total population and hospital group I, off-hour births were not associated with increased neonatal mortality and morbidities. However, in hospital group II, increased early mortality was found in the off-hour births when compared to regular-hour births. CONCLUSION: Efforts to improve the overall quality of NICU are required to lower the early mortality rate in off-hour births. Also, other sensitive indexes for the evaluation of quality of NICU care should be further studied.

Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.

BACKGROUND: There have been concerns about the development of children conceived through assisted reproductive technology. Despite multiple studies investigating the outcomes of assisted conception, data focusing specifically on the neurodevelopmental outcomes of infants conceived through assisted reproductive technology and born preterm are limited. OBJECTIVE: This study aimed to evaluate and compare the neurodevelopmental outcomes of preterm infants born at <29 weeks' gestation at 18 to 24 months' corrected age who were conceived through assisted reproductive technology and those who were conceived naturally. STUDY DESIGN: This retrospective cohort study included inborn, nonanomalous infants, born at <29 weeks' gestation between January 1, 2010, and December 31, 2016, who had a neurodevelopmental assessment at 18 to 24 months' corrected age at any of the 10 Canadian Neonatal Follow-Up Network clinics. The primary outcome was neurodevelopmental impairment at 18 to 24 months, defined as the presence of any of the following: cerebral palsy; Bayley-III cognitive, motor, or language composite score of <85; sensorineural or mixed hearing loss; and unilateral or bilateral visual impairment. Secondary outcomes included mortality, composite of mortality or neurodevelopmental impairment, significant neurodevelopmental impairment, and each component of the primary outcome. We compared outcomes between infants conceived through assisted reproductive technology and those conceived naturally, using bivariate and multivariable analyses after adjustment. RESULTS: Of the 4863 eligible neonates, 651 (13.4%) were conceived using assisted reproductive technology. Maternal age; education level; and rates of diabetes mellitus, receipt of antenatal corticosteroids, and cesarean delivery were higher in the assisted reproduction group than the natural conception group. Neonatal morbidity and death rates were similar except for intraventricular hemorrhage, which was lower in the assisted reproduction group (33% [181 of 546] vs 39% [1284 of 3318]; P=.01). Of the 4176 surviving infants, 3386 (81%) had a follow-up outcome at 18 to 24 months' corrected age. Multivariable logistic regression adjusting for gestational age, antenatal steroids, sex, small for gestational age, multiple gestations, mode of delivery, maternal age, maternal education, pregnancy-induced hypertension, maternal diabetes mellitus, and smoking showed that infants conceived through assisted reproduction was associated with lower odds of neurodevelopmental impairment (adjusted odds ratio, 0.67; 95% confidence interval, 0.52-0.86) and the composite of death or neurodevelopmental impairment (adjusted odds ratio, 0.67; 95% confidence interval, 0.54-0.84). Conception through assisted reproductive technology was associated with decreased odds of a Bayley-III composite cognitive score of <85 (adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.99) and composite language score of <85 (adjusted odds ratio, 0.67; 95% confidence interval, 0.50-0.88). CONCLUSION: Compared with natural conception, assisted conception was associated with lower odds of adverse neurodevelopmental outcomes, especially cognitive and language outcomes, at 18 to 24 months' corrected age among preterm infants born at <29 weeks' gestation. Long-term follow-up studies are required to assess the risks of learning disabilities and development of complex visual-spatial and processing skills in these children as they reach school age.

Global incidence of intraventricular hemorrhage among extremely preterm infants: a systematic literature review.

OBJECTIVES: To conduct a systematic literature review to evaluate the global incidence of intraventricular hemorrhage grade 2-4 among extremely preterm infants. METHODS: We performed searches in MEDLINE and Embase for intraventricular hemorrhage and prematurity cited in English language observational studies published from May 2006 to October 2017. Included studies analyzed data from infants born at ≤28 weeks' gestational age and reported on intraventricular hemorrhage epidemiology. RESULTS: Ninety-eight eligible studies encompassed 39 articles from Europe, 31 from North America, 25 from Asia, five from Oceania, and none from Africa or South America; both Europe and North America were included in two publications. The reported global incidence range of intraventricular hemorrhage grade 3-4 was 5-52% (Europe: 5-52%; North America: 8-22%; Asia: 5-36%; Oceania: 8-13%). When only population-based studies were included, the incidence range of intraventricular hemorrhage grade 3-4 was 6-22%. The incidence range of intraventricular hemorrhage grade 2 was infrequently documented and ranged from 5-19% (including population-based studies). The incidence of intraventricular hemorrhage was generally inversely related to gestational age. CONCLUSIONS: Intraventricular hemorrhage is a frequent complication of extremely preterm birth. Intraventricular hemorrhage incidence range varies by region, and the global incidence of intraventricular hemorrhage grade 2 is not well documented.

Umbilical Cord Milking vs Delayed Cord Clamping and Associations with In-Hospital Outcomes among Extremely Premature Infants.

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking vs delayed cord clamping among infants <29 weeks of gestation. STUDY DESIGN: Multicenter retrospective study of infants born <29 weeks of gestation from 2016 to 2018 without congenital anomalies who received active treatment at delivery and were exposed to umbilical cord milking or delayed cord clamping. The primary outcome was mortality or severe (grade III or IV) intraventricular hemorrhage (IVH) by 36 weeks of postmenstrual age (PMA). Secondary outcomes assessed at 36 weeks of PMA were mortality, severe IVH, any IVH or mortality, and a composite of mortality or major morbidity. Outcomes were assessed using multivariable regression, incorporating mortality risk factors identified a priori, confounders, and center. A prespecified, exploratory analysis evaluated severe IVH in 2 gestational age strata, 22-246/7 and 25-286/7 weeks. RESULTS: Among 1834 infants, 23.6% were exposed to umbilical cord milking and 76.4% to delayed cord clamping. The primary outcome, mortality or severe IVH, occurred in 21.1% of infants: 28.3% exposed to umbilical cord milking and 19.1% exposed to delayed cord clamping, with an aOR that was similar between groups (aOR 1.45, 95% CI 0.93, 2.26). Infants exposed to umbilical cord milking had higher odds of severe IVH (19.8% umbilical cord milking vs 11.8% delayed cord clamping, aOR 1.70 95% CI 1.20, 2.43), as did the 25-286/7 week stratum (14.8% umbilical cord milking vs 7.4% delayed cord clamping, aOR 1.89 95% CI 1.22, 2.95). Other secondary outcomes were similar between groups. CONCLUSIONS: This analysis of extremely preterm infants suggests that delayed cord clamping is the preferred practice for placental transfusion, as umbilical cord milking exposure was associated with an increase in the adverse outcome of severe IVH. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Outcomes of outborn very-low-birth-weight infants in Japan.

BACKGROUND: Outcomes of prenatal covariate-adjusted outborn very-low-birth-weight infants (VLBWIs) (≤1500 g) remain uncertain. OBJECTIVE: To compare morbidity and mortality between outborn and inborn VLBWIs. DESIGN: Observational cohort study using inverse-probability-of-treatment weighting. SETTING: Neonatal Research Network of Japan. PATIENTS: Singleton VLBWIs with no major anomalies admitted to a neonatal intensive care unit from 2012 to 2016. METHODS: Inverse-probability-of-treatment weighting with propensity scores was used to reduce imbalances in prenatal covariates (gestational age (GA), birth weight, small for GA, sex, maternal age, premature rupture of membranes, chorioamnionitis, preeclampsia, maternal diabetes mellitus, antenatal steroids and caesarean section). The primary outcome was severe intraventricular haemorrhage (IVH). The secondary outcomes were outcomes at resuscitation, other neonatal morbidities and mortality. RESULTS: The full cohort comprised 15 842 VLBWIs (668 outborns). The median (IQR) GA and birth weight were 28.9 (26.4-31.0) weeks and 1128 (862-1351) g for outborns and 28.7 (26.3-30.9) weeks and 1042 (758-1295) g for inborns. Outborn VLBWIs had a higher incidence of severe IVH (8.2% vs 4.1%; OR, 3.45; 95% CI 1.16 to 10.3) and pulmonary haemorrhage (3.7% vs 2.8%; OR, 5.21; 95% CI 1.41 to 19.2). There were no significant differences in Apgar scores, oxygen rates at delivery, intubation ratio at delivery, persistent pulmonary hypertension of the newborn, IVH of any grade, periventricular leukomalacia, chronic lung disease, oxygen at discharge, patent ductus arteriosus, retinopathy of prematurity, necrotising enterocolitis, sepsis or mortality. CONCLUSION: Outborn delivery of VLBWIs was associated with an increased risk of severe IVH.

Outcomes of Infants with Very Low Birth Weight Associated with Birthplace Difference: A Retrospective Cohort Study of Births in Japan and California.

OBJECTIVE: To determine whether outcomes among infants with very low birth weight (VLBW) vary according to the birthplace (Japan or California) controlling for maternal ethnicity. STUDY DESIGN: Severe intraventricular hemorrhage (IVH) and mortality were ascertained for infants with VLBW born at 24-29 weeks of gestation during 2008-2017 and retrospectively analyzed by the country of birth for mothers and infants (Japan or California). RESULTS: Rates of severe IVH, mortality, or combined IVH/mortality were lower in the 24 095 infants born in Japan (5.1%, 5.0%, 8.8% respectively) compared with infants born in California either to 157 mothers with Japanese ethnicity (12.5%, 9.7%, 17.8%) or to a comparison group of 6173 non-Hispanic white mothers (8.4%, 8.8%, 14.6%). ORs for adverse outcomes were increased for infants born in California to mothers with Japanese ethnicity compared with infants born in Japan for severe IVH (OR, 3.31; 95% CI, 1.93-5.68), mortality (3.73; 95% CI, 2.03-6.86), and the combined outcome (3.26; 95% CI, 2.02-5.27). The odds of these outcomes also were increased for infants born in California to non-Hispanic white mothers compared with infants born in Japan. Outcomes of infants born in California did not differ by Japanese or non-Hispanic white maternal ethnicity. CONCLUSIONS: Low rates of severe IVH and mortality for infants with VLBW born in Japan were not seen in infants born in California to mothers with Japanese ethnicity. Differences in systems of regional perinatal care, social environment, and the quality of perinatal care may partially account for these differences in outcomes.

Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care). DATA SOURCES: PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020. STUDY ELIGIBILITY CRITERIA: Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I2 statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model. RESULTS: Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2-41.6; 31 studies, 2226 infants; I2=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0-14.3; 10 studies, 374 infants; I2=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6-61.5; 5 studies, 39 infants; I2=45%; Luis Furuya-Kanamori index=-0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported. CONCLUSION: The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient-level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.

Spontaneous twin anemia polycythemia sequence: diagnosis, management, and outcome in an international cohort of 249 cases.

BACKGROUND: Twin anemia polycythemia sequence is a chronic form of unbalanced fetofetal transfusion through minuscule placental anastomoses in monochorionic twins, leading to anemia in the donor and polycythemia in the recipient. Owing to the low incidence of twin anemia polycythemia sequence, data on diagnosis, management, and outcome are limited. OBJECTIVE: This study aimed to investigate the diagnosis, management, and outcome in a large international cohort of spontaneous twin anemia polycythemia sequence. STUDY DESIGN: Data from the international twin anemia polycythemia sequence registry, retrospectively collected between 2014 and 2019, were used for this study. A total of 17 fetal therapy centers contributed to the data collection. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. RESULTS: A total of 249 cases of spontaneous twin anemia polycythemia sequence were included in this study, 219 (88%) of which were diagnosed antenatally and 30 (12%) postnatally. Twin anemia polycythemia sequence was diagnosed antenatally at a median gestational age of 23.7 weeks (interquartile range, 9.7-28.8; range, 15.1-35.3). Antenatal management included laser surgery in 39% (86 of 219), expectant management in 23% (51 of 219), delivery in 16% (34 of 219), intrauterine transfusion (with partial exchange transfusion) in 12% (26 of 219), selective feticide in 8% (18 of 219), and termination of pregnancy in 1% (3 of 219) of cases. Perinatal mortality rate was 15% (72 of 493) for the total group, 22% (54 of 243) for donors, and 7% (18 of 242) for recipients (P<.001). Severe neonatal morbidity occurred in 33% (141 of 432) of twins with twin anemia polycythemia sequence and was similar for donors (32%; 63 of 196) and recipients (33%; 75 of 228) (P=.628). Independent risk factors for spontaneous perinatal mortality were donor status (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P<.001), antenatal twin anemia polycythemia sequence stage (odds ratio, 6.3; 95% confidence interval, 1.4-27.8; P=.016 [stage 2]; odds ratio, 9.6; 95% confidence interval, 2.1-45.5; P=.005 [stage 3]; odds ratio, 20.9; 95% confidence interval, 3.0-146.4; P=.002 [stage 4]), and gestational age at birth (odds ratio, 0.8; 95% confidence interval, 0.7-0.9; P=.001). Independent risk factors for severe neonatal morbidity were antenatal twin anemia polycythemia sequence stage 4 (odds ratio, 7.9; 95% confidence interval, 1.4-43.3; P=.018) and gestational age at birth (odds ratio, 1.7; 95% confidence interval, 1.5-2.1, P<.001). CONCLUSION: Spontaneous twin anemia polycythemia sequence can develop at any time in pregnancy from the beginning of the second trimester to the end of the third trimester. Management for twin anemia polycythemia sequence varies considerably, with laser surgery being the most frequent intervention. Perinatal mortality and severe neonatal morbidity were high, the former especially so in the donor twins.

Placental transfusion and short-term outcomes among extremely preterm infants.

OBJECTIVE: To compare short-term outcomes after placental transfusion (delayed cord clamping (DCC) or umbilical cord milking (UCM)) versus immediate cord clamping among extremely preterm infants. DESIGN: Retrospective study. SETTING: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry. PATIENTS: Infants born <29 weeks' gestation in 2016 or 2017 without congenital anomalies who received active treatment after delivery. INTERVENTION/EXPOSURE: DCC or UCM. MAIN OUTCOME MEASURES: Primary outcomes: (1) composite of mortality or major morbidity by 36 weeks' postmenstrual age (PMA); (2) mortality by 36 weeks PMA and (3) composite of major morbidities by 36 weeks' PMA. Secondary composite outcomes: (1) any grade intraventricular haemorrhage or mortality by 36 weeks' PMA and (2) hypotension treatment in the first 24 postnatal hours or mortality in the first 12 postnatal hours. Outcomes were assessed using multivariable regression, adjusting for mortality risk factors identified a priori, significant confounders and centre as a random effect. RESULTS: Among 3116 infants, 40% were exposed to placental transfusion, which was not associated with the primary composite outcome of mortality or major morbidity by 36 weeks' PMA (adjusted OR (aOR) 1.26, 95% CI 0.95 to 1.66). However, exposure was associated with decreased mortality by 36 weeks' PMA (aOR 0.71, 95% CI 0.55 to 0.92) and decreased hypotension treatment in first 24 postnatal hours (aOR 0.66, 95% CI 0.53 to 0.82). CONCLUSION: In this extremely preterm infant cohort, exposure to placental transfusion was not associated with the composite outcome of mortality or major morbidity, though there was a reduction in mortality by 36 weeks' PMA. TRIAL REGISTRATION NUMBER: NCT00063063.

Antenatal diagnosis of fetal intraventricular hemorrhage: systematic review and meta-analysis.

AIM: To determine how the severity of antenatally diagnosed germinal matrix-intraventricular hemorrhage (GMH-IVH) relates to morbidity and mortality, and to explore potential risk factors. METHOD: We conducted a systematic review and individual patient data meta-analysis of antenatally diagnosed fetal GMH-IVH. The primary outcomes were mortality and morbidity. Potential associations with clinical factors during pregnancy were explored. Analysis employed Fisher's exact test and logistic regression. RESULTS: We included 240 cases from 80 studies. Presence of venous infarction was associated with mortality (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.4-13.25), motor impairment (OR 103.2, 95% CI 8.6-1238), epilepsy (OR 6.46, 95% CI 2.64-16.06), and developmental delay (OR 8.55, 95% CI 2.12-48.79). Shunt placement was associated with gestational age at GMH-IVH diagnosis and in utero progression. Many cases had uncomplicated pregnancies but possible co-occurring conditions included twin gestation, small for gestational age, and congenital anomalies. INTERPRETATION: Severity of fetal GMH-IVH, specifically venous infarction, is associated with overall mortality and morbidity. Risk factors for fetal GMH-IVH are poorly understood and controlled studies are required. WHAT THIS PAPER ADDS: Preterm germinal matrix-intraventricular hemorrhage (GMH-IVH) grading can be applied to fetuses. Many fetal germinal matrix hemorrhages occur in otherwise typical pregnancies. Half of fetuses with post-hemorrhagic ventricular dilatation receive a shunt after delivery. Fetuses with grade I or II GMH-IVH have few sequelae. Fetuses with periventricular hemorrhagic infarction have a high burden of motor impairment.

Population Improvement Bias Observed in Estimates of the Impact of Antenatal Steroids to Outcomes in Preterm Birth.

OBJECTIVE: To examine the hypothesis that increasing rates and differential uptake of antenatal steroids would bias estimation of impact of antenatal steroids on neonatal death and severe (grade III-IV) intraventricular hemorrhage (IVH). STUDY DESIGN: The study population included infants born between 24 and 28 weeks of gestational age in the California Perinatal Quality Care Collaborative. Outcomes were in-hospital mortality and severe IVH. Mixed multivariable logistic regression models estimated the effect of antenatal steroid exposure, one model accounting for individual risk factors as fixed effects, and a second model incorporating a predicted probability factor estimating overall risk status for each time period. RESULTS: The study cohort included 28 252 infants. Antenatal steroid exposure increased from 80.1% in 2005 to 90.3% in 2016, severe IVH decreased from 14.5% to 9.0%, and mortality decreased from 12.8% to 9.1%. When stratified by group, 3-year observed outcomes improved significantly in infants exposed to antenatal steroids (12.5%-8.6% for IVH, 11.5%-8.8% for death) but not in those not exposed (20.7%-19.1% and 16.6%-15.5%, respectively). Women not receiving antenatal steroids had greater risk profile (such as no prenatal care) and greater predicted probability for severe IVH and mortality. Both outcomes exhibited little change (P > .05) over time for the group without antenatal steroids. In contrast, in women receiving antenatal steroids, observed and adjusted rates for both outcomes decreased (P < .0001). CONCLUSIONS: As the population's proportion of antenatal steroid use increased, the observed positive effect of antenatal steroids also increased. This apparent increase may be designated as the "population improvement bias."

Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to prevent or treat a PDA. There are concerns regarding adverse effects of NSAIDs in preterm infants. Controversy exists on whether early targeted treatment of a hemodynamically significant (hs) PDA improves clinical outcomes. OBJECTIVES: To assess the effectiveness and safety of early treatment strategies versus expectant management for an hs-PDA in reducing mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 6) in the Cochrane Library; MEDLINE via PubMed (1966 to 31 May 2019), Embase (1980 to 31 May 2019), and CINAHL (1982 to 31 May 2019). An updated search was run on 2 October 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCT) and quasi-randomized trials. SELECTION CRITERIA: We included RCTs in which early pharmacological treatment, defined as treatment initiated within the first seven days after birth, was compared to no intervention, placebo or other non-pharmacological expectant management strategies for treatment of an hs-PDA in preterm (< 37 weeks' postmenstrual age) or low birth weight (< 2500 grams) infants. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. Our primary outcome was all-cause mortality during hospital stay. We used the GRADE approach to assess the certainty of evidence for selected clinical outcomes. MAIN RESULTS: We included 14 RCTs that enrolled 910 infants. Seven RCTs compared early treatment (defined as treatment initiated by seven days of age) versus expectant management and seven RCTs compared very early treatment (defined as treatment initiated by 72 hours of age) versus expectant management. No difference was demonstrated between early treatment versus expectant management (no treatment initiated within the first seven days after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (6 studies; 500 infants; typical RR 0.80, 95% CI 0.46 to 1.39; typical RD -0.02; 95% CI -0.07 to 0.03; moderate-certainty evidence), or other important outcomes such as surgical PDA ligation (4 studies; 432 infants; typical RR 1.08, 95% CI 0.65 to 1.80; typical RD -0.03; 95% CI -0.09 to 0.03; very low-certainty evidence), chronic lung disease (CLD) (4 studies; 339 infants; typical RR 0.90, 95% CI 0.62 to 1.29; typical RD -0.03; 95% CI -0.10 to 0.03; moderate-certainty evidence), severe intraventricular hemorrhage (IVH) (2 studies; 171 infants; typical RR 0.83,95% CI 0.32 to 2.16; typical RD -0.01; 95% CI -0.08 to 0.06; low-certainty evidence), and necrotizing enterocolitis (NEC) (5 studies; 473 infants; typical RR 2.34,95% CI 0.86 to 6.41; typical RD 0.04; 95% CI 0.01 to 0.08; low-certainty evidence). Infants receiving early treatment in the first seven days after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (2 studies; 232 infants; typical RR 2.30, 95% CI 1.86 to 2.83; typical RD 0.57; 95% CI 0.48 to 0.66; low-certainty evidence). No difference was demonstrated between very early treatment versus expectant management (no treatment initiated within the first 72 hours after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (7 studies; 384 infants; typical RR 0.94, 95% CI 0.58 to 1.53; typical RD -0.03; 95% CI -0.09 to 0.04; moderate-certainty evidence) or other important outcomes such as surgical PDA ligation (5 studies; 293 infants; typical RR 0.88, 95% CI 0.36 to 2.17; typical RD -0.01; 95% CI -0.05 to 0.02; moderate-certainty evidence), CLD (7 studies; 384 infants; typical RR 0.83, 95% CI 0.63 to 1.08; typical RD -0.05; 95% CI -0.13 to 0.04; low-certainty evidence), severe IVH (4 studies, 240 infants; typical RR 0.64, 95% CI 0.21 to 1.93; typical RD -0.02; 95% CI -0.07 to 0.04; moderate-certainty evidence), NEC (5 studies; 332 infants; typical RR 1.08, 95% CI 0.53 to 2.21; typical RD 0.01; 95% CI -0.04 to 0.06; moderate-certainty evidence) and neurodevelopmental impairment (1 study; 79 infants; RR 0.27, 95% CI 0.03 to 2.31 for moderate/severe cognitive delay at 18 to 24 months; RR 0.54, 95% CI 0.05 to 5.71 for moderate/severe motor delay at 18 to 24 months; RR 0.54, 95% CI 0.10 to 2.78 for moderate/severe language delay at 18 to 24 months; low-certainty evidence). Infants receiving very early treatment in the first 72 hours after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (4 studies; 156 infants; typical RR 1.64, 95% CI 1.31 to 2.05; typical RD 0.69; 95% CI 0.60 to 0.79; very low-certainty evidence). Very early treatment, however, shortened the duration of hospitalization compared to expectant management (4 studies; 260 infants; MD -5.35 days; 95% CI -9.23 to -1.47; low-certainty evidence). AUTHORS' CONCLUSIONS: Early or very early pharmacotherapeutic treatment of an hs-PDA probably does not reduce mortality in preterm infants (moderate-certainty evidence). Early pharmacotherapeutic treatment of hs-PDA may increase NSAID exposure (low-certainty evidence) without likely reducing CLD (moderate-certainty evidence), severe IVH or NEC (low-certainty evidence). We are uncertain whether very early pharmacotherapeutic treatment of hs-PDA also increases NSAID exposure (very low-certainty evidence). Very early treatment probably does not reduce surgical PDA ligation, severe IVH or NEC (moderate-certainty evidence), and may not reduce CLD or neurodevelopmental impairment (low-certainty evidence). Additional large trials that specifically include preterm infants at the highest risk of PDA-attributable morbidity, are adequately powered for patient-important outcomes and are minimally contaminated by open-label treatment are required to explore if early targeted treatment of hs-PDA improves clinical outcomes. There are currently two trials awaiting classification and two ongoing trials exploring this question.

Low cardiac output measured by bioreactance and adverse outcome in preterm infants with birth weight less than 1250 g.

BACKGROUND: Recently a new continuous non-invasive cardiac output measurement, bioreactance, has become available. Bioreactance measurement of cardiac output has been shown to correlate with left ventricular output detected by echocardiography in healthy term and preterm neonates. AIMS: Our aim was to correlate cardiac output measurements by bioreactance in the first 48 h of life with adverse outcomes attributable to hypoperfusion (peri/intraventricular haemorrhage (PIVH) and/or necrotising enterocolitis (NEC)) in the cohort of extremely preterm infants. STUDY DESIGN: A prospective observational cohort study. SUBJECTS: Preterm infants with birth weight less than 1250 g. OUTCOME MEASURES: Cardiac output was measured between six and 48 h of age by bioreactance. Our primary outcome was a difference in cardiac output between infants with an adverse outcome attributable to hypoperfusion (Group 1), and infants without the predefined adverse outcome (Group 2). RESULTS: There were 39 infants enrolled in the study. There were six infants in Group 1. These infants had a significantly lower minimal cardiac output measurement compared to Group 2 (mean 36.7 ml/kg/min vs 64.5 ml/kg/min, p = .0006). The mean cardiac output in Group 1 was significantly lower on day one of life, followed by a significant increase in cardiac output on day two of life compared to Group 2. CONCLUSIONS: Infants with birth weight less than 1250 g and PIVH and/or NEC had significantly lower cardiac output compared to infants without these complications on day one of life. This low cardiac output was then followed by a significant increase on day two of life.