Centralisation of very preterm deliveries and benchmarking of neonatal care

The care of very preterm infants is demanding, and the outcomes are superior when these infants are delivered in hospitals with the highest standard of care. This often requires transfer of the expectant mother when very preterm delivery is suspected. This process can be time-consuming and is potentially associated with high costs. The alternative approach includes delivering very preterm infants in hospitals that are close to the family and may provide a lower level of care, and transferring the infants to appropriate facilities after birth; this approach has been suggested to increase the risks of unfavourable outcomes. The aim of this thesis was to evaluate the costs associated with centralisation of very preterm deliveries, to assess factors that precede and facilitate centralisation, to evaluate the effect of extremely preterm birth in lower-level hospitals with and without early postnatal transfer on outcomes and to initiate international collaboration to allow for benchmarking of neonatal care outcomes. The results presented in this thesis show that centralisation of very preterm deliveries can be effectively achieved at a low cost, and identified crucial elements of the perinatal organisational pathways. The results also show that the advantage of delivering extremely preterm infants in hospitals that provide the highest level of care persists even in a setting with highly specialised neonatal transfer teams. Extremely preterm infants born in lower-level hospitals were at increased risk of adverse outcomes also without being subjected to early postnatal transfer. Within the realms of this study Finnish Medical Birth Register data were included in a multinational benchmarking collaborative, and subsequent analyses of mortality in very preterm infants showed marked variations between high-income countries. These findings indicate that centralisation of very preterm deliveries cannot be replaced by a system that relies on postnatal transfers without placing infants at severe risk. The findings also highlight the need for continuous benchmarking of neonatal outcomes and sharing of results both nationally and internationally.Pienten keskosten synnytysten keskittäminen ja hoitotulosten vertailu Pienten keskosten hoito on vaativaa, ja parhaat hoitotulokset saadaan, kun synnytykset keskitetään sairaaloihin, joissa on resursseja kaikkein pienimpien keskosten hoitamiseksi. Keskittäminen edellyttää usein raskaana olevan äidin siirtämistä korkeimman hoitotason sairaalaan ennen synnytystä, mikäli hyvin ennenaikaista synnytystä epäillään. Keskittämisprosessi voi olla haastava ja kallis. Vaihtoehtoinen ratkaisu on synnyttää pienet keskoset sairaaloissa jotka ovat lähempänä perheen kotia ja usein tarjoavat rajallisempia hoitomahdollisuuksia, ja kuljettaa vastasyntyneet keskoset varhain synnytyksen jälkeen sairaalaan jossa on mahdollista tarjota asianmukaista hoitoa; tällä mallilla on aikaisemmin ehdotettu olevan haitallisia vaikutuksia keskosille. Tämän väitöskirjan tavoitteina oli arvioida pienten keskosten synnytysten keskittämisen kustannuksia, tarkastella tekijöitä jotka edistävät keskittämistä, arvioida miten varhainen siirtokuljetus ja syntyminen alemman hoitotason sairaalassa vaikuttavat hoitotuloksiin sekä liittyä kansainväliseen pienten keskosten hoitotulosten vertailuverkostoon. Tulosten perusteella todettiin että pienten keskosten synnytysten keskittäminen oli saavutettavissa alhaisilla kustannuksilla, ja tunnistettiin tärkeitä elementtejä hoidon organisaatiossa jotka mahdollistavat keskittämisen. Erittäin pienten keskosten varhaiset siirtokuljetukset olivat yhteydessä kohonneeseen riskiin vakaviin aivoverenvuotoihin, ja syntyminen alemman hoitotason sairaaloissa ilman varhaista siirtokuljetusta kohonneeseen kuolleisuuteen. Kansainväliseen vertailuverkostoon liittymisen myötä osoitettiin, että pienten keskosten kuolleisuudessa oli merkittävää vaihtelua verkoston maiden välillä. Nämä löydökset osoittavat, että pienten keskosten synnytysten keskittämistä ei voida korvata synnytyksen jälkeisillä sairaalakuljetuksilla ilman että keskoset altistuisivat kuoleman ja vakavien aivoverenvuotojen riskeille. Löydökset korostavat myös kansainvälisen hoitotulosten vertailun ja tiedon jakamisen tärkeyttä sekä kansallisella että kansainvälisellä tasolla

Means of reaching successful antenatal transfers to level 3 hospitals in cases of threatened very preterm deliveries: a national survey

Introduction Centralization of very preterm deliveries to level 3 hospitals is recommended to improve infant survival and prevent brain injury. We studied the clinical practices of centralization from level 2 to level 3 hospitals in cases of threatening very preterm delivery in Finland. Materials and methods Obstetricians in all 16 level 2 hospitals in Finland were invited to participate in an online survey regarding antenatal transfer to level 3 hospitals among women with threatened delivery below 32 gestational weeks. We report clinical thresholds used as indications and contraindications for antenatal transfers, and logistical factors related to transfers. Results Twelve out of 16 (75%) hospitals completed the survey. The lower gestational age threshold for antenatal transfer ranged from 22 + 0 to 23 + 0 weeks. All hospitals regarded preterm premature rupture of membranes, chorioamnionitis, and severe pre-eclampsia as indications for antenatal transfer to a level 3 hospital. Most hospitals reported transferring women in spite of regular contractions (interval over 5 min) or cervical dilatation up to 4 cm. Suspicion of placental abruption, abnormal cardiotocography tracing and poor maternal condition were the most frequently reported contraindications for antenatal transfer. The time to arrange antenatal transfer was less than 2 h in all hospitals, and overcrowding of level 3 hospitals rarely hindered antenatal transfer. Conclusions Successful centralization of very preterm deliveries is reached in Finland by rapid and active antenatal transfers. This study identified clinical thresholds used by obstetricians in a setting of long distances and high centralization rate.</div

Association of early postnatal transfer and birth outside a tertiary hospital with mortality and severe brain injury in extremely preterm infants: observational cohort study with propensity score matching

Objective To determine if postnatal transfer or birth in a non-tertiary hospital is associated with adverse outcomes.Design Observational cohort study with propensity score matching.Setting National health service neonatal care in England; population data held in the National Neonatal Research Database.Participants Extremely preterm infants born at less than 28 gestational weeks between 2008 and 2015 (n=17 577) grouped based on birth hospital and transfer within 48 hours of birth: upward transfer (non-tertiary to tertiary hospital, n=2158), non-tertiary care (born in non-tertiary hospital; not transferred, n=2668), and controls (born in tertiary hospital; not transferred, n=10 866). Infants were matched on propensity scores and predefined background variables to form subgroups with near identical distributions of confounders. Infants transferred between tertiary hospitals (horizontal transfer) were separately matched to controls in a 1:5 ratio.Main outcome measures Death, severe brain injury, and survival without severe brain injury.Results 2181 infants, 727 from each group (upward transfer, non-tertiary care, and control) were well matched. Compared with controls, infants in the upward transfer group had no significant difference in the odds of death before discharge (odds ratio 1.22, 95% confidence interval 0.92 to 1.61) but significantly higher odds of severe brain injury (2.32, 1.78 to 3.06; number needed to treat (NNT) 8) and significantly lower odds of survival without severe brain injury (0.60, 0.47 to 0.76; NNT 9). Compared with controls, infants in the non-tertiary care group had significantly higher odds of death (1.34, 1.02 to 1.77; NNT 20) but no significant difference in the odds of severe brain injury (0.95, 0.70 to 1.30) or survival without severe brain injury (0.82, 0.64 to 1.05). Compared with infants in the upward transfer group, infants in the non-tertiary care group had no significant difference in death before discharge (1.10, 0.84 to 1.44) but significantly lower odds of severe brain injury (0.41, 0.31 to 0.53; NNT 8) and significantly higher odds of survival without severe brain injury (1.37, 1.09 to 1.73; NNT 14). No significant differences were found in outcomes between the horizontal transfer group (n=305) and controls (n=1525).Conclusions In extremely preterm infants, birth in a non-tertiary hospital and transfer within 48 hours are associated with poor outcomes when compared with birth in a tertiary setting. We recommend perinatal services promote pathways that facilitate delivery of extremely preterm infants in tertiary hospitals in preference to postnatal transfer.</p

Detailed prenatal and postnatal MRI findings and clinical analysis of RAF1 in Noonan syndrome

Noonan syndrome is a genetically heterogeneous developmental disorder, which usually includes findings such as short stature, facial dysmorphia, cardiac abnormalities and a varying degree of intellectual disability. We present a unique case of a rare variant of Noonan syndrome in a very preterm female infant born at 28 + 4 gestational weeks, with abnormal radiological findings visible at fetal magnetic resonance imaging (MRI) and evolution of the brain lesions during infancy

Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels -an association with mammographic density

Abstract Objective To compare the effects of tibolone and continuous combined hormone therapy on circulating sex steroids and their binding proteins and their relationship to mammographic density. Study design A prospective, double-blind placebo-controlled study. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) or placebo. Serum analyses of sex steroids, insulin-like growth factor (IGF-I) and binding proteins and assessment of mammographic breast density were performed at baseline and after 6 months of treatment. Results Estrogens were markedly increased and androgens decreased by E2/NETA. In contrast, tibolone had only a minor influence on circulating estrogens. Sex hormone binding globulin (SHBG) levels were reduced by 50%, while levels of androgens increased. Baseline values of estrone sulfate (E1S), around 1.0-1.1 nmol/l, were increased to 44.7 nmol/l by E2/ NETA and to only 1.7 nmol/l by tibolone (p 5 0.001). Mammographic breast density displayed a negative correlation with age and body mass index and a positive association with SHBG. After 6 months there was also a negative correlation with levels of free testosterone. Conclusion We found that tibolone and E2/NETA caused distinct differences in estrogen/androgen status and blood levels of possible breast mitogens. The negative association between free testosterone and mammographic density could be a possible explanation for tibolone having less influence on the breast

Unit-Level Variations in Healthcare Professionals' Availability for Preterm Neonates <29 Weeks' Gestation: An International Survey

INTRODUCTION The availability of and variability in healthcare professionals in neonatal units in different countries has not been well characterized. Our objective was to identify variations in the healthcare professionals for preterm neonates in 10 national or regional neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of neonates. METHOD Online, pre-piloted questionnaires about the availability of healthcare professionals were sent to the directors of 390 tertiary neonatal units in 10 international networks: Australia/New Zealand, Canada, Finland, Illinois, Israel, Japan, Spain, Sweden, Switzerland, and Tuscany. RESULTS Overall, 325 of 390 units (83%) responded. About half of the units (48%; 156/325) cared for 11-30 neonates/day and had team-based (43%; 138/325) care models. Neonatologists were present 24 h a day in 59% of the units (191/325), junior doctors in 60% (194/325), and nurse practitioners in 36% (116/325). A nurse-to-patient ratio of 1:1 for infants who are unstable and require complex care was used in 52% of the units (170/325), whereas a ratio of 1:1 or 1:2 for neonates requiring multisystem support was available in 59% (192/325) of the units. Availability of a respiratory therapist (15%, 49/325), pharmacist (40%, 130/325), dietitian (34%, 112/325), social worker (81%, 263/325), lactation consultant (45%, 146/325), parent buddy (6%, 19/325), or parents' resource personnel (11%, 34/325) were widely variable between units. CONCLUSIONS We identified variability in the availability and organization of the healthcare professionals between and within countries for the care of extremely preterm neonates. Further research is needed to associate healthcare workers' availability and outcomes

Trends, Characteristic, and Outcomes of Preterm Infants Who Received Postnatal Corticosteroid: A Cohort Study from 7 High-Income Countries

INTRODUCTION Our objective was to evaluate the temporal trend of systemic postnatal steroid (PNS) receipt in infants of 24-28 weeks' gestational age, identify characteristics associated with PNS receipt, and correlate PNS receipt with the incidence of bronchopulmonary dysplasia (BPD) and BPD/death from an international cohort included in the iNeo network. METHODS We conducted a retrospective study using data from 2010 to 2018 from seven international networks participating in iNeo (Canada, Finland, Israel, Japan, Spain, Sweden, and Switzerland). Neonates of 24 and 28 weeks' gestational age who survived 7 days and who received PNS were included. We assessed temporal trend of rates of systemic PNS receipt and BPD/death. RESULTS A total of 47,401 neonates were included. The mean (SD) gestational age was 26.4 (1.3) weeks and birth weight was 915 (238) g. The PNS receipt rate was 21% (12-28% across networks) and increased over the years (18% in 2010 to 26% in 2018; p &lt; 0.01). The BPD rate was 39% (28-44% across networks) and remained unchanged over the years (35.2% in 2010 to 35.0% in 2018). Lower gestation, male sex, small for gestational age status, and presence of persistent ductus arteriosus (PDA) were associated with higher rates of PNS receipt, BPD, and BPD/death. CONCLUSION The use of PNS in extremely preterm neonates increased, but there was no correlation between increased use and the BPD rate. Research is needed to determine the optimal timing, dose, and indication for PNS use in preterm neonates

Late-Onset Sepsis among Extremely Preterm Infants of 24-28 Weeks Gestation: An International Comparison in 10 High-Income Countries

INTRODUCTION: Despite advances in neonatal care, late-onset sepsis remains an important cause of preventable morbidity and mortality. Neonatal late-onset sepsis rates have decreased in some countries, while in others they have not. Our objective was to compare trends in late-onset sepsis rates in 9 population-based networks from 10 countries and to assess the associated mortality within 7 days of late-onset sepsis. METHODS: We performed a retrospective population-based cohort study. Infants born at 24-28 weeks' gestation between 2007 and 2019 were eligible for inclusion. Late-onset sepsis was defined as a positive blood or cerebrospinal fluid culture. Late-onset sepsis rates were calculated for 3 epochs (2007-11, 2012-15, and 2016-19). Adjusted risk ratios (aRRs) for late-onset sepsis were calculated for each network. RESULTS: Of a total of 82,850 infants, 16,914 (20.4%) had late-onset sepsis, with Japan having the lowest rate (7.1%) and Spain the highest (44.6%). Late-onset sepsis rates decreased in most networks and remained unchanged in a few. Israel, Sweden, and Finland showed the largest decrease in late-onset sepsis rates. The aRRs for late-onset sepsis showed wide variations between networks. The rate of mortality temporally related to late-onset sepsis was 10.9%. The adjusted mean length of stay for infants with late-onset sepsis was increased by 5-18 days compared to infants with no late-onset sepsis. CONCLUSIONS: One in 5 neonates of 24-28 weeks' gestation develops late-onset sepsis. Wide variability in late-onset sepsis rates exists between networks with most networks exhibiting improvement. Late-onset sepsis was associated with increased mortality and length of stay

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis

Objectives To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates.Design Prospective unit-level survey combined with retrospective cohort study.Setting Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy).Patients Extremely preterm infants born between 240 to 286 weeks’ gestation, with birth weightsExposures NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data.Outcome measures Surgical NEC rates and death following NEC using cohort data.Results The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%–100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%–8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks.Conclusions The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis

OBJECTIVES To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates. DESIGN Prospective unit-level survey combined with retrospective cohort study. SETTING Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy). PATIENTS Extremely preterm infants born between 24$^{0}$ to 28$^{6}$ weeks' gestation, with birth weights<1500 g, and admitted between 2014-2015. EXPOSURES NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data. OUTCOME MEASURES Surgical NEC rates and death following NEC using cohort data. RESULTS The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%-100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%-8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks. CONCLUSIONS The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research