Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasmaspecific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP $140 mmHg or diastolic BP $90 mmHg, new onset protein/creatinine ratio .0.30 g/g, and sFlt-1/placental growth factor ratio .85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

BackgroundBronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD.MethodsWe searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities.ResultsWe identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration.ConclusionsExternal validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

IMPORTANCE Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds.OBJECTIVE To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018.INTERVENTIONS Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. MAIN OUTCOME AND MEASURESThe primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. RESULTS Among 1013 patients who were randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR,16-73mL)vs19mL(IQR,0-46mL);andweeklymeanhematocritwas3percentagepointshigher withliberalthresholds.Theprimaryoutcomewasnotsignificantlydifferentbetweengroups,norwere the secondary outcomes of death, cognitive deficit, or cerebral palsy. In the liberal vs restrictive thresholds groups, respectively, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/ 485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Outcomes No./total (%) Absolute difference, % (95% CI) Odds ratio (95% CI) P value Liberal threshold Restrictive threshold Death or neurodevelopmental impairment by 24 mo 200/450 (44.4) 205/478 (42.9) 1.6 (−4.8 to 7.9) 1.05 (0.80-1.39) .72 Death by 24 mo 38/460 (8.3) 44/491 (9.0) −0.7 (−4.3 to 2.9) 0.91 (0.58-1.45) .70 Cognitive deficit 154/410 (37.6) 148/430 (34.4) 3.1 (−3.3 to 9.6) 1.12 (0.83-1.51) .47 Cerebral palsy 18/419 (4.3) 25/443 (5.6) −1.3 (−4.2 to 1.5) 0.75 (0.40-1.40) .37CONCLUSIONS AND RELEVANCE Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age.

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NIRS measurement is a simple, non-invasive method to monitor regional tissue oxygenation and the efficacy of RBC transfusion. Infants with low initial NIRS values benefited most from blood transfusions regarding SaO(2) <80%, which may be important for their general outcome.

Regulation of active Na(+) transport across fetal distal lung epithelial cells (FDLE) by corticosterone (CST), corticotropin-releasing hormone (CRH), and oxygen tension may be crucial for postnatal adaptation. FDLE isolated from 19-day rat fetuses (term: 22 days) were grown on permeable supports to confluent monolayers (duration 3 days) in 2.5, 5, 12, or 20% O(2) with 5% CO(2)-balance N(2) and mounted in Ussing chambers for measurement of short-circuit currents (I(sc)). FDLE monolayers grown in 20% O(2) had significantly higher levels of total I(sc) and of their amiloride-sensitive (I(amil)) and ouabain-sensitive (I(ouab)) components than hypoxic cells. Values (microA/cm(2) +/- SE) for 2.5-5% O(2) and 20% O(2) were, respectively, I(sc) 5.3 +/- 0.2 vs. 8.4 +/- 0.3 (P < 0.001), I(amil) 3.4 +/- 0.2 vs. 4.3 +/- 0.2 (P < 0.01), and I(ouab) 3.4 +/- 0.6 vs. 9.1 +/- 0.6 (P < 0.001). Addition of CST but not CRH to the culture medium at any O(2) concentration increased I(amil). FDLE cells grown at 5% O(2) expressed significantly lower levels of alpha-, beta-, and gamma-epithelial Na(+) channel (ENaC), and of the alpha(1)-Na(+)-K(+)-ATPase, as determined by Western blotting. We conclude that higher O(2) concentrations increased total vectorial Na(+) transport, and the function of Na(+)-K(+)-ATPase and apical amiloride-sensitive Na(+) conductance, whereas CST only increased ENaC function.

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