PRECIOUS study (PREterm Caesarean/vaginal birth and IVH/OUtcomeS): does mode of birth reduce the risk of death or brain injury in very preterm babies? A cohort and emulated target trial protocol.

INTRODUCTION: Very preterm babies are at risk of poor neurodevelopmental outcomes and death. Intraventricular haemorrhage (IVH) after birth is the most prevalent cause of this. Birth by caesarean section may protect against IVH in very preterm babies, but the evidence is limited. The aim is to identify and obtain the quantitative evidence needed to inform a future definitive clinical trial to determine the optimal mode of delivery in preterm birth. METHODS AND ANALYSIS: We will use three broad workstreams (WS) to answer complementary questions. WSs 1 and 2 involve the analysis of routinely recorded national clinical data held in an established research database. In WS1 (October 2023-March 2024), we will use conventional methods to identify what is needed to undertake a trial: the population of interest, areas of equipoise and a plausible range of effect sizes. In WS2 (April 2024-October 2024), using an emulated target trial framework, we will attempt to make inferences about the treatment effect from such a future trial and will identify potential challenges in recruitment and estimate likely 'intention-to-treat' versus 'per-protocol' profiles; these analyses will also be useful for power calculations for future possible trials. In WS3 (October 2024-March 2025), we will convene a consensus meeting with key stakeholders, supported by a clinical trials unit, to develop a multicentre clinical trial to identify the optimal mode of birth for preterm deliveries. ETHICS AND DISSEMINATION: In this study, we will use deidentified data held in the National Neonatal Research Database (NNRD), an established national population database; parents can opt out of their baby's data being held in the NNRD. HRA/Health and Care Research Wales and National Health Service (NHS) study-specific Research Ethics Committee approval (London-Queen Square Research Ethics Committee) (Ref: 23/LO/0826) ethical approval has been obtained. Key outputs of the PRECIOUS (PREterm Caesarean/vaginal birth and IVH/OUutcomeS) study include the identification of the data, and accordingly of the multidisciplinary team required, to develop, gain funding and complete, a clinical trial to definitively identify the optimal mode of delivery for preterm infants and their mothers.

Quality Improvement Interventions to Prevent Intraventricular Hemorrhage: A Systematic Review.

OBJECTIVES: Quality improvement may reduce the incidence and severity of intraventricular hemorrhage in preterm infants. We evaluated quality improvement interventions (QIIs) that sought to prevent or reduce the severity of intraventricular hemorrhage. METHODS: PubMed, CINAHL, Embase, and citations of selected articles were searched. QIIs that had reducing incidence or severity of intraventricular hemorrhage in preterm infants as the primary outcome. Paired reviewers independently extracted data from selected studies. RESULTS: Eighteen quality improvement interventions involving 5906 infants were included. Clinical interventions in antenatal care, the delivery room, and the NICU were used in the QIIs. Four of 10 QIIs reporting data on intraventricular hemorrhage (IVH) and 9 of 14 QIIs reporting data on severe IVH saw improvements. The median Quality Improvement Minimum Quality Criteria Set score was 11 of 16. Clinical intervention heterogeneity and incomplete information on quality improvement methods challenged the identification of the main reason for the observed changes. Publication bias may result in the inclusion of more favorable findings. CONCLUSIONS: QIIs demonstrated reductions in the incidence and severity of intraventricular hemorrhage in preterm infants in some but not all settings. Which specific interventions and quality improvement methods were responsible for those reductions and why they were successful in some settings but not others are not clear. This systematic review can assist teams in identifying potentially better practices for reducing IVH, but improvements in reporting and assessing QIIs are needed if systematic reviews are to realize their potential for guiding evidence-based practice.

Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants: A Randomized Clinical Trial.

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.

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.

Antenatal Risk Factors Associated with Spontaneous Intestinal Perforation in Preterm Infants Receiving Postnatal Indomethacin.

OBJECTIVE: To determine if antenatal variables affect the risk of spontaneous intestinal perforation (SIP) among preterm infants when prophylactic indomethacin is used. STUDY DESIGN: Retrospective case-control study of infants <29 weeks of gestational age between January 2010 and June 2018 at one hospital. SIP was defined as acute abdominal distension and pneumoperitoneum without signs of necrotizing enterocolitis at <14 days of life. Each case (n = 57) was matched with 2 controls (n = 114) for gestational age and birth year. Maternal and infant data were abstracted until the SIP or equivalent day for controls. Univariate analyses were followed by adjusted conditional logistic regressions and reported as OR and 95% CI. RESULTS: Mothers of cases were younger, more often delivering multiples (31% vs 14%, P = .007), and less abruptions (15% vs 29%, P = .045) but did not differ in intra-partum betamethasone, magnesium, or indomethacin use. Prophylactic indomethacin was given on day 1 to 99% of infants. SIP was associated with a shorter interval from last betamethasone dose to delivery (46 hours vs 96 hours, P = .01). Dopamine use (14% vs 4%, P = .02), volume expansion (23% vs 8%, P = .003), and high grade intraventricular hemorrhage (28% vs 8%, P = .0008) were related postnatal factors. The adjusted odds of SIP increased by 1% for each hour decrease between the last dose of betamethasone and delivery (OR 1.01, 95% CI 1.002-1.019) and with multiple births (OR 2.66, 95% CI 1.05-6.77). CONCLUSIONS: Antenatal betamethasone given shortly before delivery is associated with an increased risk of SIP. Potential interaction with medications such as postnatal indomethacin needs study.

The Effect of Antenatal Neuroprotective Magnesium Sulfate Treatment on Cerebral Oxygenation in Preterm Infants.

OBJECTIVE: Antenatal magnesium sulfate (MgSO4) treatment is associated with reduced risk of cerebral palsy in preterm infants. We aimed to investigate whether this treatment leads to any alterations on cerebral hemodynamics which could be detected by near-infrared spectroscopy (NIRS) readings in early postnatal life. STUDY DESIGN: Infants with gestational ages (GAs) ≤ 32 weeks were divided into two groups regarding their exposure to antenatal neuroprotective MgSO4 treatment or not. NIRS monitoring was performed to all infants, and readings were recorded for 2 hours each day during the first 3 days of life. The primary aim was to compare regional cerebral oxygen saturation (rcSO2) and cerebral fractional tissue oxygen extraction (cFTOE) between the groups. RESULTS: Sixty-six infants were exposed to antenatal MgSO4, while 64 of them did not. GA and birth weight were significantly lower in the treatment group (p < 0.01). No difference was observed in rcSO2 and cFTOE levels in the first, second, and the third days of life (p > 0.05). An insignificant reduction in severe intraventricular hemorrhage rates was observed (8 vs. 15%, p = 0.24). CONCLUSION: We could not demonstrate any effect on cerebral oxygenation of preterm infants in early postnatal life that could be attributed to antenatal neuroprotective MgSO4 treatment. Future studies are warranted to clarify the exact underlying mechanisms of neuroprotection.

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

BACKGROUND: Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Despite early evidence indicating a beneficial effect of antenatal corticosteroids on fetal lung maturation and widespread recommendations to use this treatment in women at risk of preterm delivery, some uncertainty remains about their effectiveness particularly with regard to their use in lower-resource settings, different gestational ages and high-risk obstetric groups such as women with hypertension or multiple pregnancies. This updated review (which supersedes an earlier review Crowley 1996) was first published in 2006 and subsequently updated in 2017. OBJECTIVES: To assess the effects of administering a course of corticosteroids to women prior to anticipated preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 September 2020), ClinicalTrials.gov, the databases that contribute to the WHO International Clinical Trials Registry Platform (ICTRP) (3 September 2020), and reference lists of the retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of antenatal corticosteroid administration with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following rupture of membranes or spontaneous labour), regardless of other co-morbidity, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness based on predefined criteria developed by Cochrane Pregnancy and Childbirth, extracted data and checked them for accuracy, and assessed the certainty of the evidence using the GRADE approach. Primary outcomes included perinatal death, neonatal death, RDS, intraventricular haemorrhage (IVH), birthweight, developmental delay in childhood and maternal death. MAIN RESULTS: We included 27 studies (11,272 randomised women and 11,925 neonates) from 20 countries. Ten trials (4422 randomised women) took place in lower- or middle-resource settings. We removed six trials from the analysis that were included in the previous version of the review; this review only includes trials that meet our pre-defined trustworthiness criteria. In 19 trials the women received a single course of steroids. In the remaining eight trials repeated courses may have been prescribed. Fifteen trials were judged to be at low risk of bias, two had a high risk of bias in two or more domains and we ten trials had a high risk of bias due to lack of blinding (placebo was not used in the control arm. Overall, the certainty of evidence was moderate to high, but it was downgraded for IVH due to indirectness; for developmental delay due to risk of bias and for maternal adverse outcomes (death, chorioamnionitis and endometritis) due to imprecision. Neonatal/child outcomes Antenatal corticosteroids reduce the risk of: - perinatal death (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; 9833 infants; 14 studies; high-certainty evidence; 2.3% fewer, 95% CI 1.1% to 3.6% fewer), - neonatal death (RR 0.78, 95% CI 0.70 to 0.87; 10,609 infants; 22 studies; high-certainty evidence; 2.6% fewer, 95% CI 1.5% to 3.6% fewer), - respiratory distress syndrome (RR 0.71, 95% CI 0.65 to 0.78; 11,183 infants; studies = 26; high-certainty evidence; 4.3% fewer, 95% CI 3.2% to 5.2% fewer). Antenatal corticosteroids probably reduce the risk of IVH (RR 0.58, 95% CI 0.45 to 0.75; 8475 infants; 12 studies; moderate-certainty evidence; 1.4% fewer, 95% CI 0.8% to1.8% fewer), and probably have little to no effect on birthweight (mean difference (MD) -14.02 g, 95% CI -33.79 to 5.76; 9551 infants; 19 studies; high-certainty evidence). Antenatal corticosteroids probably lead to a reduction in developmental delay in childhood (RR 0.51, 95% CI 0.27 to 0.97; 600 children; 3 studies; moderate-certainty evidence; 3.8% fewer, 95% CI 0.2% to 5.7% fewer). Maternal outcomes Antenatal corticosteroids probably result in little to no difference in maternal death (RR 1.19, 95% CI 0.36 to 3.89; 6244 women; 6 studies; moderate-certainty evidence; 0.0% fewer, 95% CI 0.1% fewer to 0.5% more), chorioamnionitis (RR 0.86, 95% CI 0.69 to 1.08; 8374 women; 15 studies; moderate-certainty evidence; 0.5% fewer, 95% CI 1.1% fewer to 0.3% more), and endometritis (RR 1.14, 95% CI 0.82 to 1.58; 6764 women; 10 studies; moderate-certainty; 0.3% more, 95% CI 0.3% fewer to 1.1% more) The wide 95% CIs in all of these outcomes include possible benefit and possible harm. AUTHORS' CONCLUSIONS: Evidence from this updated review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and RDS and probably reduces the risk of IVH. This evidence is robust, regardless of resource setting (high, middle or low). Further research should focus on variations in the treatment regimen, effectiveness of the intervention in specific understudied subgroups such as multiple pregnancies and other high-risk obstetric groups, and the risks and benefits in the very early or very late preterm periods. Additionally, outcomes from existing trials with follow-up into childhood and adulthood are needed in order to investigate any longer-term effects of antenatal corticosteroids. We encourage authors of previous studies to provide further information which may answer any remaining questions about the use of antenatal corticosteroids without the need for further randomised controlled trials. Individual patient data meta-analyses from published trials are likely to provide answers for most of the remaining clinical uncertainties.

Use of Antenatal Corticosteroids in Preterm Prelabor Rupture of Membranes.

"Antenatal corticosteroids are important interventions to prevent neonatal morbidity and mortality associated with preterm birth. Administering intramuscular betamethasone or dexamethasone before preterm birth reduces risks of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and death. These same benefits are seen among women with preterm prelabor rupture of membranes (PPROM) without any proven increased risk of neonatal or maternal infection. Although future studies are needed to elucidate effects of antenatal corticosteroids at less than 23 weeks' gestation and a rescue course at later gestational ages after PPROM, a single course of antenatal corticosteroids is vital to optimizing neonatal outcomes after PPROM."

Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular haemorrhage in preterm infants.

BACKGROUND: Head position during care may affect cerebral haemodynamics and contribute to the development of germinal matrix-intraventricular haemorrhage (GM-IVH) in very preterm infants. Turning the head toward one side may occlude jugular venous drainage while increasing intracranial pressure and cerebral blood volume. It is suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the infant is cared for in the supine 'head midline' position. OBJECTIVES: To assess whether head midline position is more effective than other head positions for preventing (or preventing extension) of GM-IVH in very preterm infants (< 32 weeks' gestation at birth). SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 12 September 2019), Embase (1980 to 12 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 12 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing caring for very preterm infants in a supine head midline position versus a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of haemorrhage in a subgroup of infants. We planned to analyse horizontal (flat) versus head elevated positions separately for all body positions. DATA COLLECTION AND ANALYSIS: We used standard methods of Cochrane Neonatal. For each of the included trials, two review authors independently extracted data and assessed risk of bias. The primary outcomes were GM-IVH, severe IVH, and neonatal death. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Three RCTs, with a total of 290 infants (either < 30 weeks' gestational age or < 1000 g body weight), met the inclusion criteria. Two trials compared supine midline head position versus head rotated 90° with the cot flat. One trial compared supine midline head position versus head rotated 90° with the bed tilted at 30°. We found no trials that compared supine versus prone midline head position. Meta-analysis of three trials (290 infants) did not show an effect on rates of GM-IVH (RR 1.11, 95% confidence interval (CI) 0.78 to 1.56; I² = 0%) and severe IVH (RR 0.71, 95% CI 0.37 to 1.33; I² = 0%). Neonatal mortality (RR 0.49, 95% CI 0.25 to 0.93; I² = 0%; RD -0.09, 95% CI -0.16 to -0.01) and mortality until hospital discharge (typical RR 0.50, 95% CI 0.28 to 0.90; I² = 0%; RD -0.10, 95% CI -0.18 to -0.02) were lower in the supine midline head position. The certainty of the evidence was very low for all outcomes because of limitations in study design and imprecision of estimates. We identified one ongoing study. AUTHORS' CONCLUSIONS: We found few trial data on the effects of head midline position on GM-IVH in very preterm infants. Although meta-analyses suggest that mortality might be reduced, the certainty of the evidence is very low and it is unclear whether any effect is due to cot tilting (a co-intervention in one trial). Further high-quality RCTs would be needed to resolve this uncertainty.

Cumulative effect of evidence-based practices on outcomes of preterm infants born at <29 weeks' gestational age.

BACKGROUND: Extremely preterm infants born at <29 weeks' gestational age are at high risk of death or severe neurological injury. Several individual evidence-based practices have been associated with neuroprotection. OBJECTIVE: The objective of the study was to investigate the cumulative effect of 4 evidence-based practices and their association with death and/or severe neurological injury among infants born at <29 weeks' gestational age. STUDY DESIGN: Observational study of infants born at 230-286 weeks gestational age admitted to neonatal intensive care units participating in the Canadian Neonatal Network from 2015 through 2017. We evaluated 4 practices: antenatal corticosteroids, antenatal MgSO4 for neuroprotection, deferred cord clamping ≥30 seconds, and normothermia on admission. The effect of exposure to 1, 2, 3, and all 4 evidence-based practices compared with none on death and/or severe neurological injury was assessed using multivariable logistic regression models adjusted for patient characteristics. RESULTS: Rate of death and/or severe neurological injury was 20% (873 of 4297) and varied based on exposure to evidence-based practices: none, 34% (54 of 157); 1, 27% (171 of 626); 2, 20% (295 of 1448); 3, 18% (263 of 1448); and all 4, 14% (90 of 618). Significantly lower odds of death and/or severe neurological injury were observed with exposure to antenatal corticosteroids (adjusted odds ratio, 0.52, 95% confidence interval, 0.40-0.69) and deferred cord clamping (adjusted odds ratio, 0.81, 95% confidence interval, 0.68-0.96) but not MgSO4 (adjusted odds ratio, 0.88, 95% confidence interval, 0.72-1.08) or normothermia (adjusted odds ratio, 0.96, 95% confidence interval, 0.79-1.16). Infants exposed to ≥2 evidence-based practices had significantly lower odds of death and/or severe neurological injury than those exposed to no evidence-based practices (adjusted odds ratio, 0.61, 95% confidence interval, 0.43-0.88). CONCLUSION: Among infants born at <29 weeks' gestational age, exposure to at least 2 of the evidence-based practices assessed was associated with decreased odds of death and/or severe neurological injury.

Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants.

Importance: Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. Objective: To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. Design, Setting, and Participants: Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks' gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. Interventions: Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). Main Outcomes and Measures: The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. Results: Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, -2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks' gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002). Conclusions and Relevance: In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks' gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT03019367.

What clinical practice strategies have been shown to decrease incidence rates of intraventricular haemorrhage in preterm infants?

AIM: To answer the clinical question 'In infants about to be delivered and admitted to neonatal units, what clinical practice strategies, compared to standard care, have been shown to decrease incidence rates of intraventricular haemorrhage (IVH)?' METHODS: MEDLINE via Ovid (1943 to 5 January 2018), Embase via Ovid (1974 to 5 January 2018) and the Cochrane Library (5 January 2018) were searched for relevant articles. RESULTS: A total of 478 articles, after the removal of duplicates, were found and screened by title and abstract. Forty full-text articles were subsequently reviewed, and 19 were included as relevant to the structured clinical question. An additional article was included based on expert advice. CONCLUSION: There are various levels of research evidence for clinical practice strategies to decrease the incidence rates of IVH. Higher-quality evidence suggests that antenatal corticosteroids decrease the rates of IVH, and multiple evidence-based intervention bundles implemented in the neonatal unit are associated with decreased rates of IVH.

Pharmacologic Prevention and Treatment of Neonatal Brain Injury.

Neonatal brain injury (NBI) remains a major contributor to neonatal mortality and long-term neurodevelopmental morbidity. Although therapeutic hypothermia is the only proven treatment to minimize brain injury caused by neonatal encephalopathy in term neonates, it provides incomplete neuroprotection. There are no specific drugs yet proven to prevent NBI in preterm neonates. This review discusses the scientific and emerging clinical trial data for several neuroprotective drugs in development, examining potential efficacy and safety concerns. Drugs with the highest likelihood of success and closest to clinical application include erythropoietin for term and preterm neonates and antenatal magnesium for preterm neonates.

Umbilical cord milking reduces the risk of intraventricular hemorrhage in preterm infants born before 32 weeks of gestation.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a common complication in extremely preterm infants. We aimed to demonstrate that umbilical cord milking (UCM) would reduce the incidence of IVH in this at risk population. STUDY DESIGN: We compared the incidence of IVH in a prospective cohort of consecutively born preterm infants <32 weeks' gestation receiving UCM (n = 33) with a historical cohort that underwent immediate cord clamping (ICC) (n = 36). RESULTS: No significant differences regarding perinatal characteristics were present between both groups except for chorioamnionitis and preterm rupture of membranes which were more frequent in the UCM group. There was a significant reduction in the incidence of IVH in the UCM group as compared to the ICC group (UCM vs. ICC = 12 vs. 33%, p = 0.037; OR = 0.276 (95% CI 0.079-0.967; p = 0.033; NNT = 4.7) and a reduction in the number of transfusions (UCM vs. ICC = 56 vs. 30%, p = 0.035; OR = 0.348 (0.129-0.938; p = 0.033; NNT = 3.8). UCM was safe for mothers (similar decrease in maternal hemoglobin) and offspring. CONCLUSION: UCM significantly reduced the incidence of IVH in preterm infants < 32 weeks' gestation without associated complications for mother or offspring.

Delayed clamping vs milking of umbilical cord in preterm infants: a randomized controlled trial.

BACKGROUND: It has been established that delayed umbilical cord clamping in preterm infants results in improvement in neonatal anemia, need for transfusion, incidence of necrotizing enterocolitis, and intraventricular hemorrhage by increasing neonatal circulating blood volume. However, the effects of umbilical cord milking as an alternative to delayed clamping in preterm infants are unclear. OBJECTIVE: The primary objective of this study was to compare the effect of delayed clamping vs milking of the umbilical cord on the initial hematocrit concentration in preterm births (23-34 weeks gestation). In addition, we sought to compare the effects of delayed clamping vs milking on the incidences of intraventricular hemorrhage, necrotizing enterocolitis, and need for transfusion (secondary objectives). STUDY DESIGN: The study was an unblinded randomized controlled trial of singleton preterm infants who were born 23 weeks 0 days to 34 weeks 6 days gestation and were assigned to 1 of 2 controlled study groups: delayed cord clamping for 60 seconds or milking of the cord towards the infant 4 times before clamping. Randomization occurred via block randomization with an allocation ratio of 1 to 1. The patients' third stage of delivery was standardized for route of delivery and randomization arm. All comparisons were preformed with an intent-to-treat analysis approach. The study was powered at 80% with a probability value of .05 for the primary outcome measure of a hematocrit difference of 3% between the 2 groups. RESULTS: Of the 204 randomized patients, 104 were assigned to the delayed subgroup, and 100 were assigned to the milking subgroup. There were no significant differences in baseline maternal characteristics noted between groups. Though there was not any statistically significant difference in neonatal outcomes between the cord clamping and milking groups, the occurrences of transfusion (15.5% vs 9.1%; P=.24), necrotizing enterocolitis (5.8% vs 3.0%; P=.49), and intraventricular hemorrhage (15.5% vs 10.1%; P=.35) were all lower in the milking group. The milking group had higher initial hematocrit concentration compared with the delayed clamping group, although this was not significant (51.8 [6.2%] vs 49.9 [7.7%]; P=.07]. Peak bilirubin levels and need for phototherapy were similar between groups. CONCLUSION: This study demonstrates that milking the umbilical cord may be an acceptable alternative to delayed cord clamping because there were similar effects on neonatal hematocrit concentrations and the need for neonatal transfusions and no increased risk for complications or neonatal morbidity. The present data support the concept that milking of the umbilical cord may offer an efficient and timely method of providing increased blood volume to the infant.

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial.

Importance: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Design, Setting, and Participants: Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results: Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance: Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

[IVH Prevention for ELBW Preterm Babies in Two Different Perinatal Centers]. / IVH-Prävention bei ELBW-Frühgeborenen in zwei Perinatalzentren.

BACKGROUND: In a project to carefully observe and minimize risk factors of intraventricular hemorrhages (IVH) in preterm infants, the incidence decreased markedly at the perinatal Center in Ulm, Germany. By comparing its data with the perinatal center in Leipzig, Germany, we sought to identify what improvements could still be made. METHODS: A retrospective survey was performed, including 189 infants from Leipzig and 89 from Ulm, all of whom weighed less than 1000 grams. A comparison between both perinatal centers was made. RESULTS: IVH was more frequently detected in Leipzig (28.4%) than in Ulm (14.6%, p=0.011), yet only the incidence of mild IVH (grade 1-2) was affected since the incidence of severe IVH did not differ between the 2 centers (p=0.59, Leipzig 6.1%, Ulm 4.5%). Furthermore, several potentially avoidable risk factors of IVH were differentially distributed between the 2 centers. For example, postnatal hypocapnia and postnatal hypothermia occurred with higher frequency in Leipzig than in Ulm. Conversely, rapid postnatal application of surfactant was the rule in Leipzig but not in Ulm. Furthermore, sodium bicarbonate application occurred more frequently in Ulm. CONCLUSION: Both centers avoided certain risk factors for IVH with varying success. These results allow both centers to specifically target the risk factors that occurred with greater frequency to further reduce the incidence of IVH.

Short- and long-term neonatal outcomes according to differential exposure to antenatal corticosteroid therapy in preterm births prior to 24 weeks of gestation.

AIM: To assess the effects of differential exposure to antenatal corticosteroid (ACS) on short- and long-term outcomes of infants born before 24 weeks of gestation. METHODS: This is a retrospective cohort study of 147 infants delivered by 116 women at 21-23 weeks of gestation between January 2001 and December 2016 at a tertiary referral hospital in Seoul, Korea. Eligible subjects were categorized into the following three groups according to ACS exposure: non-user (n = 53), partial-course (n = 44), and complete-course (n = 50). Univariable and multivariable analyses were used to compare neonatal mortality, neonatal morbidities including intraventricular hemorrhage (IVH), and neurodevelopmental impairment including cerebral palsy among the three groups. RESULTS: Neonatal mortality rate was significantly lower in the ACS-user groups (non-user, 52.8%; partial-course, 27.3%; complete-course, 28.0%; P = 0.01), but complete-course of ACS therapy had no advantages over partial-course. A lower incidence of IVH was observed in the complete-course group (non-users, 54.8%; partial-course, 48.6%; complete-course, 20.5%; P = 0.003). Multiple logistic regression analysis showed that ACS therapy, either partial- or complete-course, was associated with a lower rate of neonatal mortality (adjusted odds ratio (aOR) 0.375; 95% confidence interval (CI) 0.141-0.996 in partial-course; aOR 0.173; 95% CI 0.052-0.574) in complete-course). IVH (aOR 0.191; 95% CI 0.071-0.516) was less likely to occur in the complete-course group than in the non-user group. Neurodevelopmental impairment of survivors at 18-22 month after birth was not significantly different among the three groups. CONCLUSION: ACS therapy in preterm births at 21-23 weeks of gestation was associated with significantly reduced rates of neonatal mortality and IVH, especially with complete administration.

[Impact of screening and treatment of low systemic blood flow in the prevention of severe intraventricular haemorrhage and/or death in pre-term infants]. / Impacto del cribado y tratamiento del bajo flujo sistémico en la prevención de hemorragia intraventricular grave y/o muerte en el prematuro.

OBJECTIVE: To assess the effect of a protocolised intervention for low systemic blood flow (SBF) in the occurrence of severe intraventricular haemorrhage (IVH) or death in pre-term infants. METHODS: A study with a quasi-experimental design with retrospective controls was conducted on pre-term infants of less than 30weeks of gestational age, born between January 2016 and July 2017, who were consecutively included in the intervention period. The control cohort included pre-term infants (born between January 2013 and December 2015) matched by gestational age, birth weight, and gender (two controls for each case). The cases of low SBF diagnosed according to functional echocardiography during the study period received dobutamine (5-10µg/kg/min) for 48hours. RESULTS: The study included 29 cases (intervention period) and 54 controls (pre-intervention period). Ten out of 29 (34.5%) infants received dobutamine for low SBF during the intervention period, with 3/29 (10.3%) cases of severe IVH and/or death compared to 17/54 (31.5%) in the control cohort (p=.032). There was an independent association between the intervention and a decreased occurrence of severe IVH/death after adjusting for confounding factors both in the logistic regression model [OR 0.11 (95%CI: 0.01-0.65), p=.015], as well as in the sensitivity analysis using inverse probability of treatment weighting [OR 0.23 (95%CI: 0.09-0.56); p=.001]. CONCLUSIONS: In this study with retrospective controls, a protocolised screening, and treatment for low SBF was associated with a decreased occurrence of severe IVH or death in preterm infants. Large, adequately powered trials, are needed in order to determine whether postnatal interventions directed at low SBF can improve neurological outcomes.

Antenatal corticosteroids in impending preterm deliveries before 25 weeks' gestation.

Antenatal corticosteroid (ANC) use before 25 weeks' gestation is controversial. Our previous systematic review (eight observational studies, n=10 109) showed that ANC exposure was associated with significantly reduced mortality and severe intraventricular haemorrhage (IVH)/periventricular leukomalacia (PVL) in neonates born <25 weeks. We update our review by adding data (n=3334) from a recent study. We used Cochrane methodology and summarised the results using GRADE (The Grading of Recommendations Assessment, Development and Evaluation) guidelines. Nine high-quality observational studies were included. Meta-analysis (random effects model) showed reduced mortality (n=13 443; OR=0.48 (95% CI 0.42 to 0.55) P<0.00001; level of evidence (LOE): moderate) and IVH or PVL (n=8418; OR=0.70 (95% CI 0.63 to 0.79), P<0.00001; LOE: moderate) in neonates born <25 weeks exposed to ANC. There was no difference in necrotising enterocolitis (NEC) ≥stage II (n=8737; OR=1.01 (95% CI 0.84 to 1.22), P=0.89; LOE: low); incidence of chronic lung disease (CLD) was higher (n=7983; OR=1.32 (95% CI 1.04 to 1.67), P=0.02; LOE: low) in ANC group. Composite outcomes of death/major morbidities (eg, severe IVH, NEC, CLD) were improved after ANC exposure.