Major Neurodevelopmental Disability Research Articles

Neonatal magnesium sulphate for neuroprotection: A systematic review and meta-analysis.

To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE). This was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability). Twenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision. Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries.

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age

ObjectiveTo clarify the relationships of three definitions of severity of bronchopulmonary dysplasia (BPD) with adverse neurodevelopmental and respiratory outcomes at early school-age. Study designParticipants comprised 218 consecutive survivors to 7-8 years of age born either <28 weeks’ gestation or weighing <1000 g in Victoria, Australia, in 2005. BPD was classified as none, Grade 1 (mild), Grade 2 (moderate), or Grade 3 (severe), using two commonly accepted definitions: 1) Jobe2001, and 2) Higgins2018, and our own 3) VICS2005, adapted from Jensen2019. Outcomes included major neurodevelopmental disability, low intelligence quotient and academic achievement, poor motor function, and poor respiratory function as assessed by spirometry. Outcomes for children with each grade of BPD were compared with children with no BPD. ResultsOf the 218 survivors, 132 (61%) had BPD on Jobe2001 criteria, and 113 (52%) had BPD on both Higgins2018 and VICS2005 criteria. Grade 1 on any criteria was not associated with any adverse neurodevelopmental outcomes. Grade 1 on both Higgins2018 and VICS2005 was associated with reduced spirometry. Grade 2 on both Higgins2018 and VICS2005, and Grade 3 on all criteria were associated with increased risk for both adverse neurodevelopmental and respiratory outcomes. ConclusionsCompared with no BPD, receiving additional oxygen up to 29% but no positive pressure support at 36 weeks’ postmenstrual age increased the risk of abnormal respiratory function but not adverse neurodevelopment. Receiving ≥30% oxygen or any positive pressure support at 36 weeks increased the risk of both adverse outcomes.

Perinatal asphyxia and hypothermic treatment from the endocrine perspective.

Perinatal asphyxia is one of the three most important causes of neonatal mortality and morbidity. Therapeutic hypothermia represents the standard treatment for infants with moderate-severe perinatal asphyxia, resulting in reduction in the mortality and major neurodevelopmental disability. So far, data in the literature focusing on the endocrine aspects of both asphyxia and hypothermia treatment at birth are scanty, and many aspects are still debated. Aim of this narrative review is to summarize the current knowledge regarding the short- and long-term effects of perinatal asphyxia and of hypothermia treatment on the endocrine system, thus providing suggestions for improving the management of asphyxiated children. Involvement of the endocrine system (especially glucose and electrolyte disturbances, adrenal hemorrhage, non-thyroidal illness syndrome) can occur in a variable percentage of subjects with perinatal asphyxia, potentially affecting mortality as well as neurological outcome. Hypothermia may also affect endocrine homeostasis, leading to a decreased incidence of hypocalcemia and an increased risk of dilutional hyponatremia and hypercalcemia. Metabolic abnormalities in the context of perinatal asphyxia are important modifiable factors that may be associated with a worse outcome. Therefore, clinicians should be aware of the possible occurrence of endocrine complication, in order to establish appropriate screening protocols and allow timely treatment.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

Diagnostic accuracy of small-for-gestational-age status for infant mortality and school-age outcomes of live births

ObjectivesTo determine the diagnostic accuracy of small-for-gestational-age (SGA; <10th centile) status for infant mortality and adverse school-age outcomes in infants born extremely preterm (EP; <28 weeks’ gestation).DesignGeographical cohort studies.SettingThe state...

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Systemic opioid regimens for postoperative pain in neonates.

Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, and cross-over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre-term or full-term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta-analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence). None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive- and educational-related outcomes. AUTHORS' CONCLUSIONS: Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent- or nurse-controlled analgesia.

Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants.

Germinal matrix-intraventricular haemorrhage (GMH-IVH) and encephalopathy of prematurity (EoP) remain substantial issues in neonatal intensive care units worldwide. Current therapies to prevent or treat these conditions are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. This is an update of the 2019 review, which did not include EoP. To evaluate the benefits and harms of stem cell-based interventions for prevention or treatment of GM-IVH and EoP in preterm infants. We used standard, extensive Cochrane search methods. The latest search was April 2022. We attempted to include randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing 1. stem cell-based interventions versus control; 2. mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; 3. stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or 4. MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH or EoP; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH or with EoP. We used standard Cochrane methods. Our primary outcomes were 1. all-cause neonatal mortality, 2. major neurodevelopmental disability, 3. GM-IVH, 4. EoP, and 5. extension of pre-existing non-severe GM-IVH or EoP. We planned to use GRADE to assess certainty of evidence for each outcome. We identified no studies that met our inclusion criteria. Three studies are currently registered and ongoing. Phase 1 trials are described in the 'Excluded studies' section. No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment or prevention of GM-IVH or EoP in preterm infants. We identified three ongoing studies, with a sample size range from 20 to 200. In two studies, autologous cord blood mononuclear cells will be administered to extremely preterm infants via the intravenous route; in one, intracerebroventricular injection of MSCs will be administered to preterm infants up to 34 weeks' gestational age.

Systemic opioid regimens for postoperative pain in neonates.

Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, and cross-over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre-term or full-term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta-analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence). None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive- and educational-related outcomes. AUTHORS' CONCLUSIONS: Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent- or nurse-controlled analgesia.

Perinatal risk factors for developmental coordination disorder in children born extremely preterm.

Children born extremely preterm frequently have developmental coordination disorder (DCD). We aimed to evaluate perinatal risk factors for DCD. Swedish national cohort study including 226 children born before 27 gestational weeks without major neurodevelopmental disabilities at 6.5 years. Outcome was DCD, defined as ≤5th percentile on the Movement Assessment Battery for Children-Second Edition. Perinatal risk factors were evaluated using multivariable logistic regression. DCD was present in 84/226 (37.2%) children. Of the risk factors known at 40 weeks gestation, independent and significant risk factors for DCD were: mother's age at delivery (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.80); pre-eclampsia (2.79, 1.14-6.80); mother born in a non-Nordic country (2.23, 1.00-4.99); gestational age per week increase (0.70, 0.50-0.99) and retinopathy of prematurity (2.48, 1.26-4.87). Of factors known at discharge, postnatal steroids exposure (2.24, 1.13-4.46) and mechanical ventilation (1.76, 1.06-2.09) were independent risk factors when added to the model in separate analyses. The risk of DCD in children born extremely preterm was multifactorial and associated with gestational age largely mediated by ROP, maternal factors, pre-eclampsia, administration of postnatal steroids and mechanical ventilation. These risk factors are common among children born extremely preterm, contributing to their high risk of DCD.

Magnesium Sulfate as an Adjunct to Therapeutic Hypothermia in the Management of Term Infants with Hypoxic-Ischemic Encephalopathy: A Randomized, Parallel-Group, Controlled Trial.

To evaluate whether magnesium sulfate and therapeutic hypothermia in combination decreases mortality and/or major neurodevelopmental disability at 1 y of age among term neonates with hypoxic-ischemic encephalopathy. A total of 134 term neonates were randomized to receive intravenous magnesium sulfate at a dose of 250mg/kg (at 8mg/kg/min) once daily for 3 d starting within 6h after birth along with therapeutic hypothermia in the intervention group and therapeutic hypothermia alone in the comparator group. The primary outcome was the composite outcome of mortality and/or major neurodevelopmental disability (Developmental Assessment Scale for Indian Infants score < 70) at 1 y of age. A total of 115 infants were included in the primary analysis. The composite primary outcome occurred in 14 (24%) infants in the intervention group and 19 (33%) infants in the comparator group, and the difference was not statistically significant (p = 0.30; relative risk 0.72; 95% confidence interval 0.40-1.30). The secondary outcomes including neonatal mortality, major neurodevelopmental disability at 1 y of age, neurological status at discharge, level of oxidative stress markers, and adverse effects including hypotension and respiratory depression requiring support were also comparable between the groups. The combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and/or major neurodevelopmental disability at 1 y of age. Clinical Trials Registry of India (CTRI/2018/06/014594), prospectively registered.

Scaffolding Parenting and Health Development for Preterm Flourishing Across the Life Course.

Advances in obstetrics and neonatal medicine have resulted in improved survival rates for preterm infants. Remarkably, >75% extremely (<28 weeks) preterm infants who leave the NICU do not experience major neurodevelopmental disabilities, although >50% experience more minor challenges in communication, perception, cognition, attention, regulatory, and executive function that can adversely impact educational and social function resulting in physical, behavioral, and social health issues in adulthood. Even late premature (32-36 weeks) infants have more neurodevelopmental challenges than term infants. Although early intervention and educational programs can mitigate risks of prematurity for children's developmental trajectories, restrictive eligibility requirement and limitations on frequency and intensity mean that many premature infants must "fail first" to trigger services. Social challenges, including lack of family resources, unsafe neighborhoods, structural racism, and parental substance use, may compound biological vulnerabilities, yet existing services are ill-equipped to respond. An intervention system for premature infants designed according to Life Course Health Development principles would instead focus on health optimization from the start; support emerging developmental capabilities such as self-regulation and formation of reciprocal secure early relationships; be tailored to each child's unique neurodevelopmental profile and social circumstances; and be vertically, horizontally, and longitudinally integrated across levels (individual, family, community), domains (health, education), and time. Recognizing the increased demands placed on parents, it would include parental mental health supports and provision of trauma-informed care. This developmental scaffolding would incorporate parenting, health, and developmental interventions, with the aim of improved health trajectories across the whole of the life course.

Trends in survival, perinatal morbidities and two-year neurodevelopmental outcomes in extremely low-birthweight infants over four decades.

Although outcomes for infants born extremely low birthweight (ELBW; <1000g birthweight) have improved over time, it is important to document survival and morbidity changes following the advent of modern neonatal intensive care in the 1990s. To describe trends in survival, perinatal outcomes and neurodevelopment to 2years' corrected age over time across six discrete geographic cohorts born ELBW between 1979 and 2017. Analysis of data from discrete population-based prospective cohort studies of all live births free of lethal anomalies with birthweight 500-999g in the state of Victoria, Australia, over 6 eras: 1979-80, 1985-87, 1991-92, 1997, 2005 and 2016-17. Perinatal data collected included survival, duration and type of respiratory support, neonatal morbidities and two-year neurodevelopmental outcomes. More ELBW live births were inborn (born in a maternity hospital with a neonatal intensive care unit) over time (1979-80, 70%; 2016-17, 84%), and more were offered active care (1979-80, 58%; 2016-17, 90%). Survival to 2years rose substantially, from 25% in 1979-80 to 80% in 2016-17. In survivors, rates of any assisted ventilation rose from 75% in 1979-80 to 99% in 2016-17. Cystic periventricular leukomalacia, severe retinopathy of prematurity and blindness improved across eras. Two-year data were available for 95% (1054/1109) of survivors. Rates of cerebral palsy, deafness and major neurodevelopmental disability changed little over time. The annual numbers with major neurodevelopmental disability increased from 12.5 in 1979-80 to 30 in 2016-17, but annual numbers free of major disability increased much more, from 31 in 1979-80 to 147 in 2016-17. Active care and survival rates in ELBW children have increased dramatically since 1979 without large changes in neonatal morbidities. The numbers of survivors free of major neurodevelopmental disability have increased more over time than those with major disability.

Disparities between perceived and true outcomes of infants born at 23-25 weeks' gestation.

Decision-making for infants born at 23-25weeks involves counselling parents about survival and major disability risks. Accurate information is needed for parents to make informed decisions about their baby's care. To determine if perinatal clinicians had accurate perceptions of outcomes of infants born at 23-25weeks' gestation, and if accuracy had changed over a decade. A web-based survey was sent to midwives, nurses, neonatologists, and obstetricians working in tertiary and non-tertiary hospitals, and the neonatal retrieval service in the state of Victoria in 2020. A similar survey had been completed in 2010. Clinicians' estimates of survival and major neurodevelopmental disability rates were compared with true rates for actively managed infants overall, and by infant birthplace and gestational age, and professional workplace and discipline. Accuracy of outcomes was compared between eras. Overall, 165 surveys were received. Participants underestimated survival (absolute mean difference [%] -14.4%; [95% confidence interval (CI) -16.6 to -12.3]; P<0.001) and overestimated major disability (absolute mean difference 32.7%; [95% CI 29.7 to 35.8]; P<0.001) rates overall, and at each week of gestation, and were worse for outborn compared with inborn infants. Perceptions of clinicians in tertiary centres were similar to those of non-tertiary clinicians. Nurses/midwives were more pessimistic, and paediatricians were more optimistic. Clinicians' perceptions of outcome were less accurate in 2020 than in 2010. Most perinatal clinicians underestimate survival and overestimate major disability of infants born at 23-25weeks' gestation, which may translate into overly pessimistic counselling of parents.

Changes in long-term survival and neurodevelopmental disability in infants born extremely preterm in the post-surfactant era

Extremely preterm birth before 28 weeks’ gestation accounts for less than 1% of births in high-income countries but is associated with high rates of perinatal and infant mortality, and of neurodevelopmental disability in surviving children. Survival rates have increased over time, both overall, and within each week of gestational age since the introduction of exogenous surfactant into clinical care in the early 1990s. However, rates of major neurodevelopmental disability in survivors, whether they be in early childhood or at school-age, have not clearly improved in parallel with the increases in survival. An important strategy to improve survival free of major neurodevelopmental disability is to birth extremely preterm infants in a tertiary perinatal center, where specialist obstetric care for the mother and ongoing intensive care for the infant can both be provided without the potential morbidities associated with postnatal transfer.

Temporal Trends in Neurodevelopmental Outcomes to 2 Years After Extremely Preterm Birth

Survival of infants born extremely preterm (EP) (<28 weeks' gestation) has increased since the early 1990s. It is necessary to know whether increased survival is accompanied by increased neurodevelopmental disability. To examine changes in major (ie, moderate or severe) neurodevelopmental disability and survival free of major neurodevelopmental disability at 2 years in infants born EP. Four prospective longitudinal cohort studies comprising all EP live births at 22 to 27 weeks' gestation from April 1, 2016, to March 31, 2017, and earlier eras (1991-1992, 1997, and 2005), and contemporaneous term-born controls in the state of Victoria, Australia. Among 1208 live births during the periods studied, data were available for analysis of 2-year outcomes in 1152 children: 422 (1991-1992), 215 (1997), 263 (2005), and 252 (2016-2017). Data analysis was performed from September 17, 2020, to April 15, 2021. Extreme preterm live birth. Survival, blindness, deafness, cerebral palsy, developmental delay, and neurodevelopmental disability at 2 years' corrected age. Developmental delay comprised a developmental quotient less than -1 SD relative to the control group means on the Bayley Scales for each era. Major neurodevelopmental disability comprised blindness, deafness, moderate to severe cerebral palsy, or a developmental quotient less than -2 SDs. Individual neurodevelopmental outcomes in each era were contrasted relative to the 2016-2017 cohort using logistic regression adjusted for gestational age, sex, birth weight z score, and sociodemographic variables. Changes in survival free of major neurodevelopmental disability over time were also assessed using logistic regression. Survival to 2 years was highest in 2016-2017 (73% [215 of 293]) compared with earlier eras (1991-1992: 53% [225 of 428]; 1997: 70% [151 of 217]; 2005: 63% [170 of 270]). Blindness and deafness were uncommon (<3%). Cerebral palsy was less common in 2016-2017 (6%) than in earlier eras (1991-1992: 11%; 1997: 12%; 2005: 10%). There were no obvious changes in the rates of developmental quotient less than -2 SDs across eras (1991-1992: 18%; 1997: 22%; 2005: 7%; 2016-2017: 15%) or in rates of major neurodevelopmental disability (1991-1992: 20%; 1997: 26%; 2005: 15%; 2016-2017: 15%). Rates of survival free of major neurodevelopmental disability increased steadily over time: 42% (1991-1992), 51% (1997), 53% (2005), and 62% (2016-2017) (odds ratio, 1.30; 95% CI, 1.15-1.48 per decade; P < .001). These findings suggest that survival free of major disability at age 2 years in children born EP has increased by an absolute 20% since the early 1990s. Increased survival has not been associated with increased neurodevelopmental disability.

Fetoscopic compared with open repair of myelomeningocele: a 2-delivery cost-effectiveness analysis

Recent studies have compared maternal and neonatal outcomes associated with fetoscopic surgical approach for repair of myelomeningocele compared with an open approach. In this study, we compared the cost-effectiveness of these techniques in the setting of a woman seeking future pregnancies. A decision-analytical model using TreeAge software was designed to compare the costs and outcomes of fetoscopic vs open repair in patients with prenatally diagnosed myelomeningocele. We assumed a theoretical cohort of 500 women with a pregnancy affected by myelomeningocele planning to have a future pregnancy. Our model accounted for costs and quality-adjusted life years of the woman, the neonate with myelomeningocele, and the neonate in a subsequent pregnancy. Neonatal outcomes from the incident pregnancy included motor function >2 levels better than the anatomic level, motor function <2 levels better than the anatomic level, and same motor function as the anatomic level, preterm birth in the index pregnancy, neonatal death in the index pregnancy, and major neurodevelopmental disability as a result of preterm birth in the index pregnancy. Neonatal outcomes in the subsequent pregnancy included stillbirth, preterm birth, and neonatal and major neurodevelopmental disability as a result of preterm birth. Probabilities were derived from the literature, and we used a willingness-to-pay threshold of $100,000 per quality-adjusted life year. In the index pregnancy, fetoscopic surgical technique resulted in 140 fewer cases of preterm birth and fewer cases of neurodevelopmental disability and neonatal death. Fetoscopic technique resulted in 130 more cases of functional level >2 levels better than the anatomic level, 35 fewer cases of functional level >2 levels worse than the anatomic level, and 107 fewer cases of function same as the anatomic level. In the subsequent pregnancy, fetoscopic surgery led to 22 fewer cases of delivery complications (uterine dehiscence, uterine rupture, and excessive bleeding), 24 fewer cases of stillbirth, and 22 fewer cases of preterm birth. Although the fetoscopic approach was more costly, it was cost-effective with an incremental cost-effectiveness ratio of $1029 per quality-adjusted life year in our theoretical cohort of 500 patients. Monte Carlo probabilistic sensitivity analysis showed that fetoscopic technique is cost-effective 100% of the time. In our theoretical cohort, the fetoscopic approach was more costly, but resulted in improved outcomes when a subsequent pregnancy was considered.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, and preterm infants peri‐extubation. To determine the effects of early versus late discontinuation of caffeine administration on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, and preterm infants peri‐extubation.

Interventions to minimize blood loss in very preterm infants-A systematic review and meta-analysis.

Blood loss in the first days of life has been associated with increased morbidity and mortality in very preterm infants. In this systematic review we included randomized controlled trials comparing the effects of interventions to preserve blood volume in the infant from birth, reduce the need for sampling, or limit the blood sampled. Mortality and major neurodevelopmental disabilities were the primary outcomes. Included studies underwent risk of bias-assessment and data extraction by two review authors independently. We used risk ratio or mean difference to evaluate the treatment effect and meta-analysis for pooled results. The certainty of evidence was assessed using GRADE. We included 31 trials enrolling 3,759 infants. Twenty-five trials were pooled in the comparison delayed cord clamping or cord milking vs. immediate cord clamping or no milking. Increasing placental transfusion resulted in lower mortality during the neonatal period (RR 0.51, 95% CI 0.26 to 1.00; participants = 595; trials = 5; I2 = 0%, moderate certainty of evidence) and during first hospitalization (RR 0.70, 95% CI 0.51, 0.96; 10 RCTs, participants = 2,476, low certainty of evidence). The certainty of evidence was very low for the other primary outcomes of this review. The six remaining trials compared devices to monitor glucose levels (three trials), blood sampling from the umbilical cord or from the placenta vs. blood sampling from the infant (2 trials), and devices to reintroduce the blood after analysis vs. conventional blood sampling (1 trial); the certainty of evidence was rated as very low for all outcomes in these comparisons. Increasing placental transfusion at birth may reduce mortality in very preterm infants; However, extremely limited evidence is available to assess the effects of other interventions to reduce blood loss after birth. In future trials, infants could be randomized following placental transfusion to different blood saving approaches. Trial registration: PROSPERO CRD42020159882.

297 Fetoscopic compared to open repair of myelomeningocele: a two-delivery cost-effectiveness analysis

In this study, we compared the cost-effectiveness of the fetoscopic surgical approach for repair of myelomeningocele (MMC) as compared to an open approach in the setting of a woman seeking future pregnancies. A decision-analytic model was designed to compare the costs, and outcomes of fetoscopic versus open repair in patients with prenatally diagnosed MMC. We used a theoretical cohort of 100 women with a pregnancy affected by MMC planning to have a future pregnancy. Neonatal outcomes from the incident pregnancy included motor function more than two levels better than anatomic level, motor function less than two levels better than anatomic level and same motor function as anatomic level, preterm birth in the index pregnancy, neonatal death in the index pregnancy, and major neurodevelopmental disability in the index pregnancy. Neonatal outcomes in the subsequent pregnancy included spontaneous abortion, preterm birth, neonatal and major neurodevelopmental disability. Probabilities were derived from the literature, and we used a willingness-to-pay threshold of $100,000 per QALY. Fetoscopic surgery resulted in 9 additional cases of preterm birth in the index pregnancy, resulting in an increase in neonatal death and neurodevelopmental disability as a result of preterm birth, in addition to the functional deficit from the MMC. In the subsequent pregnancy, fetoscopic surgery led to nine fewer cases of delivery complications (uterine dehiscence, uterine rupture and excessive bleeding), 17 fewer spontaneous abortions, 7 fewer cases of preterm birth, resulting in decreased cases of neurodevelopmental disability and neonatal death. While the fetoscopic approach was more costly, it was cost effective with an ICER of $69,800/QALY in our theoretical cohort of 100 patients. Univariate sensitivity analysis showed that as the chance of having a subsequent pregnancy increases, the ICER decreases due to lower costs and higher QALYs. In our theoretical cohort, the fetoscopic approach was more costly, but resulted in improved outcomes when a subsequent pregnancy was considered.View Large Image Figure ViewerDownload Hi-res image Download (PPT)