Willem de Boode Artificial Womb - Venticare€¦ · Vol 388 December 17/24/31, 2016 3029 averted to...

Kunstmatige baarmoederDroom of ’binnenkort’ werkelijkheid?

Willem P. de Boode, kinderarts-neonatoloogRadboudumc Amalia Kinderziekenhuis, Nijmegen

Ontwikkelingen in de neonatale zorgBelangrijkste mijlpalen• Antenataal corticosteroiden• Exogene surfactanttoediening• Beademingsstrategieën, zoals

hoogfrequente ventilatie, ‘gentleventilation’, volume-gestuurde beademing, non-invasieve ondersteuning van de ademhaling

• Selectieve pulmonale vaatverwijding (NO-inhalatie)

Ontwikkelingen in de neonatale zorg• Grens van levensvatbaarheid verschuift naar 22-23 weken

zwangerschapsduur• Overleving van extreem prematuur geboren baby’s is verbeterd• Echter, geen afname van complicaties van vroeggeboorte, zoals

bijvoorbeeld bronchopulmonale dysplasie

Consequenties van vroeggeboorteImmaturiteitBonchopulmonary dysplasia

Longbloeding

HersenbloedingHerseninfarct

Ontwikkelingsstoornis

VoedingsproblemenNecrotiserende enterocolitis

HypoglycemieNierfalen

AfweerstoornisSepsis

Infectie

HartfalenPersisterende ductus arteriosus

Hypotensie/shock

Mader: Understanding Human Anatomy & Physiology, Fifth Edition

II. Support, Movement, and Protection

7. The Muscular System © The McGraw−Hill Companies, 2004

7.1 Functions and Typesof MusclesAll muscles, regardless of the particular type, can contract—that is, shorten. When muscles contract, some part of thebody or the entire body moves. Humans have three types ofmuscles: smooth, cardiac, and skeletal (Fig. 7.1). The contrac-tile cells of these tissues are elongated and therefore are calledmuscle fibers.

Smooth MuscleSmooth muscle is located in the walls of hollow internal or-gans, and its involuntary contraction moves materialsthrough an organ. Smooth muscle fibers are spindle-shapedcells, each with a single nucleus (uninucleated). The cells areusually arranged in parallel lines, forming sheets. Smoothmuscle does not have the striations (bands of light and dark)seen in cardiac and skeletal muscle. Although smooth muscleis slower to contract than skeletal muscle, it can sustain pro-longed contractions and does not fatigue easily.

Cardiac MuscleCardiac muscle forms the heart wall. Its fibers are uninucle-ated, striated, tubular, and branched, which allows the fibersto interlock at intercalated disks. Intercalated disks permit

contractions to spread quickly throughout the heart. Cardiacfibers relax completely between contractions, which preventsfatigue. Contraction of cardiac muscle fibers is rhythmical; itoccurs without outside nervous stimulation or control. Thus,cardiac muscle contraction is involuntary.

Skeletal MuscleSkeletal muscle fibers are tubular, multinucleated, and stri-ated. They make up the skeletal muscles attached to the skele-ton. Skeletal muscle fibers can run the length of a muscle andtherefore can be quite long. Skeletal muscle is voluntary be-cause its contraction is always stimulated and controlled bythe nervous system. In this chapter, we will explore why skele-tal muscle (and cardiac muscle) is striated.

Connective Tissue Coverings

Muscles are organs, and as such they contain other types of tis-sues, such as nervous tissue, blood vessels, and connective tis-sue. Connective tissue is essential to the organization of thefibers within a muscle (Fig. 7.2). First, each fiber is surroundedby a thin layer of areolar connective tissue called the endomy-sium. Blood capillaries and nerve fibers reach each musclefiber by way of the endomysium. Second, the muscle fibers aregrouped into bundles called fascicles. The fascicles have asheath of connective tissue called the perimysium. Finally, the

114 Part II Support, Movement, and Protection

Figure 7.1 Types of muscles. The three types of muscles in the body have the appearance and characteristics shown here.

Smooth muscle• has spindle-shaped, nonstriated, uninucleated fibers.• occurs in walls of internal organs.• is involuntary.

Cardiac muscle• has striated, tubular, branched, uninucleated fibers.• occurs in walls of heart.• is involuntary.

Skeletal muscle• has striated, tubular, multinucleated fibers.• is usually attached to skeleton.• is voluntary.

Iatrogene schade

Consequenties van vroeggeboorte

Figure 1. Gestational Age Specific Survival for Extremely Preterm InfantsCharacteristics of the data sources are shown in Table 1.

Patel Page 15

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www.thelancet.com Vol 388 December 17/24/31, 2016 3029

averted to the remaining causes pro rata. The cause-specific deaths averted were calculated as the product of the following four quantities: 1) cause-specific deaths estimated by VAMCM before post-hoc adjustment, 2) the fractions due to vaccine-specific serotypes, 3) vaccine coverage, and 4) vaccine effectiveness, where available, or efficacy. Details of the parameters used in the post-hoc adjustment are available in the appendix (p 7). Lastly, a 7-year moving-average smoother was applied to the national-level prediction covariates used in the VAMCM to attenuate implausible spikes due to systematic errors in measurement or inconsistencies in covariate definitions.

Model selection and uncertainty estimationWe selected the final model by cross validation. Specifically, we selected 10% of the observed cause-of-death data points, and fit each of the candidate models using the remaining 90%. We then predicted the CSMFs in the withheld selection, and determined the difference between the observed and predicted estimates. We repeated this process with 500 random subsets. We selected as final the model with the smallest average out of sample prediction error.13,16

We estimated uncertainty in model coefficients by bootstrap resampling of input data sets from all estimation components and their respective distributions. This uncertainty was propagated through to the model predictions.13,17 Uncertainty in the estimates of under-5 and neonatal deaths was also included using the UN-IGME methodology.1 We also accounted for potential variability due to post-hoc adjustment and the modelled number of deaths due to measles, pertussis, HIV, and malaria outside of sub-Saharan Africa. The 2·5 and 97·5 percentiles were taken as the lower and upper ranges of the uncertainty.

Estimates reportingEstimates of deaths in the 1–59 month period due to preterm birth complications, intrapartum-related events, and congenital abnormalities were produced previously, but were collapsed into the category of other. They are reported separately here. Notably, the number of deaths due to, for example, congenital abnormalities among under-5 is then the sum of the numbers of deaths due to congenital abnormalities among neonates and 1–59-month-olds. Other conditions among children aged 1–59 months include causes originated during the perinatal period, cancer, severe malnutrition, and other specified causes.

Since we estimated child mortality by cause for 2000–15 but not for 1990–99, we were not able to assess cause-specific progress toward the MDG 4 for the entire period of 1990–2015. However, we can benchmark cause-specific progress in 2000–15 with the 4·4% average annual rate of reduction (ARR) required to achieve the MDG 4.8,18 We also present the aggregated cause-of-death profile by six U5MR strata using the 2015 estimates with the cutoffs of

10, 25, 50, 75, and 100 per 1000 livebirths, referred to as very low, low, medium, medium high, high, and very high mortality strata, respectively.1

To promote transparency and replicability of global health estimates, we have also included the GATHER reporting checklist in the appendix (p 9).19 Additional details of the input data, estimation methodology including statistical codes, and estimates are online and publicly available through the Maternal and Child Epidemiology Estimation’s website.

Role of the funding sourceThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and the corresponding author had final responsibility for the decision to submit for publication.

New input data Total input data

Data points Deaths Countries Data points Deaths Countries

Neonates

VR 298 355 666 58 1628 1 621 273 66

VRMCM 674 772 904 64 2004 2 038 511 66

VAMCM 12 1897 5 124 100 119 37

1–59-month-olds

VR 166 412 925 69 1104 2 043 763 69

VRMCM 147 288 535 58 1364 1 646 909 68

VAMCM 90 49 214 18 218 372 324 42

VR=vital registration. VRMCM=VR based multi-cause model. VAMCM=VA based multi-cause model.

Table 1: New and total input data by estimation methods

Congenital (3·5%)

Other (11·0%)

Pneumonia (12·8%)

Intrapartum-relatedevents (0·9%)

Preterm (15·9%)

Other (2·5%)Injury (0·6%)

Congenital (5·1%)

Sepsis ormeningitis (6·8%)

Intrapartum-related events (10·7%)

Pneumonia (2·7%)

Tetanus (0·6%)

Diarrhoea (0·3%)Diarrhoea (8·6%)Measles (1·2%)

Injury (5·5%)

Malaria (5·2%)

AIDS (1·4%)Meningitis (1·9%)Pertussis (0·9%)Preterm (1·9%)

Neonatal death (45·1%)1–59 months (54·9%)

Figure 1: Global causes of under-5 deaths in 2015

For Maternal and Child Epidemiology Estimations see http://tinyurl.com/Hopkins-MNCH-cod-openaccess

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nally, after consecutive deduction of infants withspecific NICU complications (sequentially minustreated ROP, CLD, duct ligation, and surgical necro-tizing enterocolitis [NEC] or gut perforation) fromthe corresponding groups of surviving infants free ofneurologic sequelae, 28% of the infants with a gesta-tion of 26 weeks could be defined as short-term intactsurvivors. For the infants of 25 and 24 weeks’ gesta-tion, 7% and 4% are left as intact survivors, repre-senting 6 of 90 and 2 of 54 admitted infants, respec-tively.

Short-term outcome of the 175 infants who weredischarged alive in different NICUs is shown in Fig4. Fifty-eight percent (!20) is the median (!IQR) rateof survival without serious neuromorbidity. The me-dian (!IQR) survival rate without any major neuro-logic sequelae and also free of NICU-related compli-cations is 20% (!21).

All 3 of the major adverse outcomes—serious neu-romorbidity, CLD at 36 weeks’ postmenstrual age,and treated ROP—occurred in 10 (6%) infants, and 2of the 3 adversities occurred in 40 (23%) other infants(Fig 5). One of these 3 major adverse outcomes wasobserved in another 61 (20%) infants who were dis-charged from the hospital. The occurrence of "1 ofthese major adverse outcome variables was signifi-cantly higher in the group of admitted infants with agestation of 24 to 25 weeks compared with the ad-mitted group with a gestational age of 26 weeks (!2,P # .014). Of the 35 surviving infants with thresholdROP, 74% (26 of 35) had at least 1 major comorbidity.Surgical duct ligation was an isolated specific eventin 4 surviving infants, and laparotomy for NEC orbowel perforation was a single complication for 9

other infants. Of the 19 surviving infants with asurgical duct closure, 74% were oxygen dependent at36 weeks’ postmenstrual age.

Logistic regression analysis was performed usingthe same independent variables as in the previousanalysis with, at this time, serious neuromorbidity(intracranial hemorrhage [ICH] grade 3 or 4, cysticperiventricular leukomalacia [PVL], and dischargedisability present or suspect) and typical NICU-re-lated complications (treated ROP, CLD at 36 weeks’

Fig 3. Cumulative short-term outcome scale at the time of discharge for admitted infants with a GA of 24 to 26 weeks. Severe neurologicsequelae are ICH grade 3 and 4 or shunted hydrocephaly (ICH "3), cystic PVL (cPVL), and discharge disability present or suspected(disdis). NICU-related complications are treated ROP (tROP), CLD at 36 weeks’ postmenstrual age (CLD36), surgical ligation of PDA(sPDA), and surgical NEC (sNEC) or IP.

Fig 4. Short-term outcome of the 175 infants who were dischargedalive: box-and-whisker plots (median ! IQR) for survival withoutmajor neuromorbidity (58% ! 20; A), survival without severeneurologic sequelae and without tROP (46% ! 21; B), survivalwithout neuromorbidity, tROP, and CLD (28% ! 23; C), andsurvival without neuromorbidity, tROP, CLD, and sPDA orNEC/IP (20% ! 21; D).

668 THE EPIBEL STUDY by guest on May 31, 2019www.aappublications.org/newsDownloaded from

Vanhaesebrouck P, Allegaert K, Bottu J, Debauche C, Devlieger H, Docx M, et al. The EPIBEL study: outcomesto discharge from hospital for extremely preterm infants in Belgium. Pediatrics. 2004;114(3):663-75.



p _ p J y ,

Acta Pædiatrica ISSN 0803–5253

EDITORIAL

The hard problemHugo Lagercrantz ([email protected])Acta Paediatrica, Astrid Lindgren Cildren’s Hospital, Stockholm, Sweden

CorrespondenceHugo Lagercrantz, Acta Paediatrica BuildingX5:01,Astrid Lindgren Children’s Hospital,SE-171 76 Stockholm, Sweden.Tel: +46 8 517 728 25/517 724 87|Email: [email protected]

DOI:10.1111/j.1651-2227.2007.00640.x

The survival of extremely preterm infants (<26 gestationalweeks) has increased considerably during the last decades.In a national study from the United Kingdom and Ireland,all of these tiny infants born in 1995 have been followed up(EPICure). Of these infants, 46% were found to be severelyor moderately disabled at 30 months (1). There is a concernthat the improved survival of extremely preterm infants willincrease the incidence of adverse neurodevelopmental out-come. In this issue, Wyatt et al. at the University CollegeLondon report a progressive survival of these infants from32% to 71% between 1981 and 2000 (2). In spite of these ex-cellent survival results, there was no increase of impairmentleading to disability (2). Two Swedish studies have also re-ported less neurological complications than the British Na-tional Survey (3,4).However, even if more severe cerebral complications such

as severe intraventricular haemorrhage (IVH) or white mat-ter injury with cysts can be avoided, there is still a risk for

22 24 26 28 30 32 34 36 38 40 4250

60

70

80

90

100

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24 73 144 27 23 39 67 92 103 162 252 397 414 348 415 465 917 289 100

n=

Mean +SEM

Gestational age (w)

Kau

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C M

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Figure 1 The relationship between intelligence quote IQ and gestational age. The figure is based on metaanalysis. Published with the kind permission of D. Wolkeand N. Marlow (6)

delayed brain maturation, particularly myelination. An in-verse relationship between cognitive score and gestationalage has been found when tested at school age (Fig. 1)(1,5,6).The Nuffield Council on Bioethics (7) concluded that in-

fants born at 25 weeks or above have a good prognosis andshould receive intensive care. Even if they are between 24and 25 weeks, they should be offered full intensive care andsupport from birth. However, if the condition deteriorates,treatment should not continue against the will of the par-ents. If the infants are between 23 and 24 weeks, precedenceshould be given to the wishes of the parents.An alternative view is that the limit of human viability

might be defined as the stage when a foetus or a preterminfant is able to be conscious, although at a minimal level.The thalamocortical connections start to function aroundthe 25th gestational week, but not before that (8). Todemonstrate that they are conscious according to traditional

142 C⃝2008 The Author/Journal Compilation C⃝2008 Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 142–143

Lagercrantz H. The hard problem. Acta Paediatr. 2008;97(2):142-3.

clear preterm behavioural phenotype characterised by attention,anxiety and social difficulties has emerged.36 Although preva-lence estimates for clinically significant problems vary widelyusing parent-completed or teacher-completed rating scales,25

prevalence estimates for psychiatric disorders are more consist-ent at 23%–24%37 38 equating to a 3 times increased risk com-pared with term-born controls.25 39 This behavioural phenotypeis also evidenced in the pattern of psychiatric disorders observedin EP cohorts, in which there is a significant excess of ADHD(typically symptoms of inattention rather than hyperactivity/impulsivity), emotional disorders (typically anxiety rather thandepression) and ASD (typically problems with social interactionand communication).36 Notably, the excess of these disordersoccurs in the absence of an increased risk for conduct disorders,a pattern that is also observed using behavioural rating scales.40

The international and temporal consistency in outcomes sug-gests that universal biological factors underlie the developmentof behavioural, social and emotional problems in this popula-tion, and the association of psychiatric disorders with cognitiveimpairments and indices of brain structure and function suggeststhat these may be mediated by adverse neurodevelopment fol-lowing EP birth.36 38 41 Studies have also shown that the com-monly observed deficits in executive functions described abovemay mediate the relationship between EP birth and psychiatricmorbidity, in particular, attention problems.29 42–44

Educational outcomesLarge population-based studies of the effects of gestation atbirth have shown that EP children are less likely to completebasic school education and are more likely to have poorer aca-demic attainment than both their term-born peers and theirmore mature preterm counterparts.45 46 Birth cohort studieshave also shown that these deficits are evident on both standar-dised attainment tests14 47–50 and teacher reports23 49–51 andfrom the earliest years of schooling throughout adolescence.There are also significantly and substantially increased rates oflearning difficulties,14 47 48 52 even among those without neuro-sensory impairments and after adjustment for socioeconomicfactors. Consequently, 39%–62% of EP/ELBW children arereported to have special educational needs (SEN);14 47 52 thus,it is unsurprising that after neonatal care the greatest costs asso-ciated with support for EP children lie in education.53

Data from the UK EPICure Study of births <26 weeks gesta-tion illustrate the deficits observed in educational outcomes. At6 years of age, 50% of EP children were rated by teachers ashaving below average attainment compared with 5% of term-born classmates (OR 17.9, 95% CI 8.3 to 38.9),54 with asimilar deficit observed at 11 years of age (50% vs 5%; OR

18.2, 95% CI 8.0 to 41.4).51 Attainment in all school subjectswas also significantly poorer than term-born controls (figure 2).Overall, 30% of EP children had learning difficulties in readingversus 2% of their term-born classmates (OR 22; 95% CI 6.6 to7.0) and 44% versus 1.3% had mathematics learning difficulties(OR 59; 95% CI 14 to 243).14 These data and those of otherstudies show that of all subjects studied at school, EP childrenappear to have greatest difficulties in mathematics (figure 2)47 52

and, unlike reading difficulties, these are not fully accounted forby low IQ. Similar to the findings relating to behavioural out-comes, specific deficits in executive functions may also underlieVP children’s difficulties with mathematics.43 52 55

OUTCOMES IN ADULTHOODThe majority of data relating to outcomes in adulthood are pro-vided by registry-based studies or are from VP/VLBW cohortsassembled in the 1970s and 1980s. Although these have fewerEP survivors than contemporary cohorts, they do provide anindex of what we might expect life to be like for EP adultstoday. These typically show a clear gestational age-related gradi-ent in outcomes with EP adults remaining at increased risk forCP and other neurosensory disabilities.56–59 Recent reports alsoshow that VP/VLBW adults do not outgrow their cognitive pro-blems and that deficits are still present to a similar magnitudeas in earlier assessments, including significantly poorer per-formance on tests of IQ and executive functions and increasedrates of intellectual disabilities.60 61 The profile of cognitiveabilities in early adulthood is also similar to that reported inchildhood.61

The educational attainment of VP/VLBW young adults is alsogenerally poorer than term-born adults with fewer completinghigher education and a greater proportion opting to undertakevocational education or training.59 61 There is also evidence ofan increased risk for psychiatric disorders in adulthood, includ-ing ASD,59 ADHD62 63 and mood disorders59 64 65 demonstrat-ing continuity with outcomes reported in childhood (figure 3).A number of studies have also reported reduced social interac-tions and risk-taking behaviours in VP/VLBW adolescents66 67

and higher introversion, autistic features and neuroticism whichmay underpin some of the social difficulties in this population.Fewer VP/VLBW adults are also married or cohabiting andreproductive rates may be lower than observed in term-bornadults.57 Longitudinal studies have also shown that cognitiveand behavioural problems in VP/VLBW individuals are morestable over time than in adults born at term.60 68

Despite the persistence of health and neurodevelopmentalsequelae, VP/VLBW adults are perhaps functioning better thanmight have once been expected with a significant majority

Figure 2 Mean difference (95% CI)in teacher ratings of academicattainment for 145 extremely pretermchildren (<26 weeks gestation) and171 term-born controls assessed at11 years of age in the UK & IrelandEPICure Study.51

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leading independent and self-supportive lives.57 Although VP/VLBW adults may have lower wealth and job-related income,they have similar rates of employment to term-born adults56 59

and self-perceived quality of life is similar to controls with manymanaging the transition to adulthood as well as adults born atmore mature gestations.57 These results are encouraging and theclinical and academic communities are eagerly anticipating pub-lication of outcomes in adulthood for the earliest EP cohortsassembled in the 1990s and beyond.

IMPLICATIONS FOR INTERVENTIONThe persistence of neurodevelopmental sequelae from infancyto adulthood underscores the need for preventive intervention.Increased recognition of the association of sensitive and respon-sive parenting with later school-age outcomes suggests that inter-ventions to improve parent–infant interaction might bebeneficial.69 However, evidence for the efficacy of post-dischargeprogrammes for enhancing cognitive and developmental out-comes is limited; even where short-term effects have beenreported, these are rarely sustained beyond the period of inter-vention delivery and into school age.70 In recent years, attentionhas turned to the potential for working memory training toimprove cognitive and educational outcomes in preterm popula-tions. However, although these might show short-term gain interms of improved working memory, there is as yet no evidenceof generalisation to other outcomes either in preterm children orthose with working memory deficits.71 72 Given the heterogeneityin outcomes and the wide range of deficits experienced by EPchildren, interventions that are delivered during the school yearsand those that target the multiple cognitive processes affected byEP birth may be beneficial. Such efforts might focus on the devel-opment of new population-specific interventions or on triallingthe efficacy of existing teaching strategies in EP children.

Given the preterm behavioural phenotype described above,EP children are often characterised as anxious and inattentive,but not as hyperactive or disruptive in the classroom. As such,

EP children with difficulties may not come to the teacher’sattention as readily as other children with externalising behav-iour problems or with other SEN. Thus, informing educationprofessionals about the special constellation of problems follow-ing EP birth may help them to identify those with difficultiesand provide appropriate support in the classroom.73 From aparent’s perspective, delaying school entry might be consideredas a potential intervention to help improve their child’s per-formance at school, especially for those who feel their child isdevelopmentally immature and/or is born in the summermonths. However, recent evidence suggests that delaying schoolentry is unlikely to benefit preterm children’s academic attain-ment and that starting school at the age-appropriate time andensuring support for those with difficulties may be more appro-priate.74 However, more research is needed to provide a defini-tive answer as to whether delaying school entry might benefitchildren’s academic, emotional and social outcomes in the longterm.

CONCLUSIONSImproved survival rates for EP births over recent decades havenot yet been matched by clear evidence of a reduction in ratesof neurodevelopmental disability. A high prevalence of intellec-tual disabilities, behavioural, social and emotional problems andlearning difficulties continues to dominate the literature relatingto childhood outcomes and recent reports have confirmed thatthese difficulties persist into adult life. Neuropsychological defi-cits appear to mediate the relationship between EP birth andlong-term outcomes and may represent potential targets forintervention, though evidence for the long-term efficacy of earlyintervention efforts remains limited. Longitudinal studies withfollow-up into adulthood are needed to determine the impact ofEP birth in relation to contemporary care and to identifywhether ongoing improvements in neonatal medicine havetranslated into improved outcomes across the lifespan. Althougha substantial proportion of EP survivors are likely to need inter-vention to facilitate their performance at school and to support

Figure 3 Psychiatric morbidity inadolescents and young adults bornvery preterm (figure created using datafrom Lindstrom et al64 ).

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Johnson S, Marlow N. Early and long-term outcome of infants born extremely preterm.

Arch Dis Child. 2017;102(1):97-102.

IQ SchoolprestatiesPsychiatrischeproblematiek

Consequenties van vroeggeboorte• De gestoorde ontwikkeling van de longen bij BPD lijkt met name te

berusten op een te vroege overgang van vloeistof-gevulde longen naar gas-gevulde longen

• Zoektocht naar een meer fysiologische ondersteuning van een extreem prematuur met als doel• voortzetting van de foetale groei en ontwikkeling,• zonder de iatrogene schade door postnatale intensive care interventies,• leidend tot een verbetering in overleving èn kwaliteit van leven voor

kritisch zieke prematuren

Artificial placenta

• Reeds 50 jaar onderwerp van onderzoek

• Nog maar weinig succesvol

Artificial placenta/womb

Artificial placentaProblemen:1. Progressief cardiocirculatoir falen door

veranderingen in zowel preload als afterload van het hart (weerstand oxygenator, gebruik van pomp met extracorporeel circuit)

2. Gebruik van open “couveuses” met risico op contaminatie en sepsis

3. Vaatspasmen bij het verkrijgen van vasculaire toegang

Ideale kunstmatige placentaDe ideale kunstmatige

placenta komt overeen met het ‘natuurlijke’ foeto-

placentaire systeem, waarbij de perfusie bepaald wordt

door de foetale cardiac output

Foetale circulatie

EXTEND - EXTrauterine Environment for Neonatal Development

Partridge EA, Davey MG, Hornick MA, McGovern PE, Mejaddam AY, Vrecenak JD, et al. An extra-uterinesystem to physiologically support the extreme premature lamb. Nat Commun. 2017;8:15112.

post-membrane oxygen tension to supraphysiologic levels. Wetherefore next turned our attention to achieving exclusive cannu-lation of the umbilical vessels, adopting an approach utilizing bothumbilical arteries in addition to a single umbilical vein. Our tech-nique for umbilical cannulation maintains a length of native um-bilical cord (5e10 cm) between the cannula tips and the abdominalwall, both to minimize the possibility of cannula kinking orobstruction in addition to providing native vessel length to permitvasoreactivity to accommodate pressure changes across thearterio-venous shunt imposed by the circuit. Vasospasm of the cordvessels during cannulation was regularly observed, but was miti-gated by a combination of topical papaverine administration,atraumatic operative technique, and maintaining warmth andphysiologic (low) oxygen saturation of the umbilical venous inflowon initiation of circuit flow.

The results of experiments utilizing exclusive umbilical cordcannulation have been remarkable, with maintenance of stablecircuit flow rates equivalent to the normal flow to the placenta(150e200 mL/kg/min) and evidence of normal growth, oxygendelivery, and organ maturation (Fig. 1) [27]. Fetuses ranging in agefrom 105 to 120 days gestation have been maintained in stablephysiologic condition for 20e28 days. Daily erythropoietinadministration was found to slow the progression of anemia withreduction or elimination of the need for blood transfusion. Dailyechocardiography confirmed physiologic cardiac outputs andmaintenance of the fetal cardiac circulation throughout the um-bilical artery/umbilical vein runs, with near-normal ductus arte-riosus flows, and right-to-left shunting through the foramen ovale.Cardiac contractility was excellent, and chamber and vena cava sizecould be used as an indicator of general volume status, allowingadjustments in fluid administration. Nutrition provided via thecircuit was based on substrate uptake of late-gestation fetal lambs[28,29], and consisted predominantly of carbohydrate and aminoacid, with trace lipid content. Titration of dextrose and amino acidadministration was correlated with levels of plasma glucose(<40 mg/dL) and BUN (<30 mg/dL) to avoid an osmotic diuresisand/or hyperosmolar state. Substrate tolerance generally correlatedwith oxygen delivery, and at relatively higher oxygen delivery,lambs tolerated physiologic levels of substrate delivery anddemonstrated growth comparable to breed-matched controls. Fetalbreathing movements were noted regularly throughout the

incubation period, and correlated with the partial pressure of car-bon dioxide measured in the systemic circulation. From a qualita-tive perspective, there was obvious growth and maturation withprolonged runs. Animals opened their eyes, became more active,had apparently normal breathing and swallowing movements,grew wool, and clearly occupied a greater proportion of spacewithin the incubator. Lung maturation was quantified by detailedmorphometric analysis, histologic assessment for surfactant pro-tein B, and analysis of function after birth. Morphometric analysisdemonstrated progression from the canalicular to saccular stages oflung development in parallel with age-matched normal controllambs. From a functional perspective, lambs were easily ventilatedafter removal from the circuit, and nearly comparable to 141-daygestational-age control lambs delivered by cesarean section andimmediately ventilated. Brainswere grossly normal after runs, withnormal histology, normal weight, and no evidence of hemorrhageor infarct on whole sectioning. Runs were terminated at 28 daysdue to animal protocol limitations rather than any evidence ofinfection or hemodynamic instability, suggesting that support ofthese early gestation animals could be maintained beyond fourweeks. Since our initial report, we have achieved survival off allmechanical support in two lambs supported on EXTEND for 21 and29 days. Each was weaned from mechanical ventilation over a 12 hperiod and were feeding and growing normally. One succumbed toa pyelonephritis at 12 days of independent life, and the other is nowaged three months and thriving with apparently normal neurologicdevelopment.

Supplementary video related to this article can be found athttp://dx.doi.org/10.1016/j.siny.2017.04.006.

These results demonstrate physiologic support of extreme pre-mature fetal lambs for up to four weeks without evidence of iat-rogenic injury, metabolic or physiologic derangements, or therequirement for pressor support. Our findings are superior to allprevious attempts at extracorporeal support of the extreme pre-mature fetus in both duration and physiologic wellbeing, andsupport continued development of the system for application tohuman clinical intervention. Fetal lambs at 105e115 days corre-spond developmentally to the clinical target of 23e25 weeksgestation in the human infant. At present, the morbidity andmortality affecting infants born at this stage of prematurity justifiesclinical application of extracorporeal support of the premature

Fig. 1. Current EXTEND prototype highlighting the three critical components (see Supplemantary Video 1 online).

E.A. Partridge et al. / Seminars in Fetal & Neonatal Medicine 22 (2017) 404e409 407

Drie essentiële componenten• Arterioveneus circuit met lage

weerstand zonder pomp• Gesloten steriele vloeistof omgeving

(‘Biobag’) met continue verversing van het kunstmatige vruchtwater

• Specifieke techniek voor het verkrijgen van toegang tot de navelstrengvaten

Partridge EA, Davey MG, Hornick MA, Flake AW. An EXTrauterine environment for neonatal development: EXTENDING fetal physiology beyond the womb. Semin Fetal Neonatal Med. 2017;22(6):404-9.



First succesful reportof the use of an ‘artificial

womb’ in a series of 8 lambs



LICULamb Intensive Care Unit

• Canulatieprocedure kan binnen 2 minuten (!) tussen instrumentatie en start bloed flow door extracorporeel circuit

• Gemodificeerde EXIT-procedure noodzakelijk, waarbij de navelstreng(vaten) kunnen worden benaderd voor canulatie



• Stabiele bloedflow door extracorporele circuit overeenkomstig met normale foetale transplacentaire bloedflow (150-200 mL/kg/min)

• Fysiologisch zuurstoftransport en -aanbod• Dagelijks erythropoiëtine (EPO) toediening





UA/UV lambs

such access is required, and lack of rapid access in the case of anemergency. In our system, we can examine the fetus in greatdetail by ultrasound that is superior to physical examination, andcan access the circuit for all our vascular access needs

(haemodynamic monitoring, blood draws and fluid/nutritionalsupport). Sterile access ports for suction of meconium and otherpurposes are included, and we have designed a clinical device thatcould be rapidly opened should the fetus need to be resuscitated.

Control † GA 105–111 days

In utero(GA 125 d) 1

NA 106

621

11.4

156

79.4

18.3

6.5

34.7

44.4

24.7

54.3

8.3

7.42

0.8

60b

d

a

c

e

30

0

7.7

7.4pH

7.1

0 350 700 00

Hae

mog

lobi

n (g

dl–1

)

12

20Lambs 4–8 (EPO)

Lambs 1–3 (no EPO)

350 700

*

00.0

Pla

sma

lact

ate

(mm

ol l–1

)

1.5

3.0

350 7000 350Time (h) Time (h)

700

PaCO2

PaO2

0.8

7.39

7.1

51.2

21.9

39.3

42.4

42.2 40.9

34.1

39.7

40.042.3

10.0

23.8

88.4

190

10.4 9.8 12.7 10.8

194 179 226

87.9 72.5 77.4

22.3 22.4 26.3

9.4 7.6 10.2

25.8 20.6 19.9

50.3 48.3 46.9

6.6 8.3 6.9

7.38 7.36 7.38

0.9 1.0 1.4

669 600 672 627

106105 110 111

NA

Gestational age (days) at cannulation

2 3 7 8 4Mean ±s.e.m.

9.0 ± 1.0

233 ± 40

83.2 ± 5.1

108 ± 1

638 ± 14

11.0 ± 0.5

189 ± 11

81.1 ± 3.1

22.6 ± 1.3

8.7 ± 0.7

38.7 ± 1.8

41.3 ± 1.8

22.6 ± 1.1

50.2 ± 1.3

7.4 ± 0.4

7.39 ± 0.01

1.0 ± 0.1

22.3 ± 2.2

7.0 ± 2.7

32.8 ± 7.5

44.9 ± 2.7

20.7 ± 2.0

54.6 ± 4.5

6.6 ± 0.8

7.39 ± 0.04

1.8 ± 0.5

Mean ±s.e.m.5 6

GA 115–120 days

Duration of run (h)

Haemoglobin (g dl–1)

‘Circuit’ flow per weight (ml kg–1min–1)

Post-membrane O2 saturation (%)

Total O2 delivery (ml kg–1min–1)

Total O2 consumption (ml kg–1min–1)

Total O2 extraction (%)

Umbilical artery PaCO2 (mm Hg)

Umbilical artery PaO2 (mm Hg)

Umbilical artery O2 saturation (%)

Umbilical artery O2 content (ml dl–1)

Umbilical artery pH

Plasma lactate (mmol l–1)

116

468

14.7

135

85.6

23.0

9.4

41.5

43.1

20.8

50.2

9.9

7.35

1.0

116

678

14.2

142

87.7

23.5

8.2

35.1

43.2

21.9

57.6

11.0

7.39

1.0 0.9

7.37

8.9

54.2

22.7

39.5

43.5

9.1

21.2

94.7

134

12.2 13.7 ± 0.8

137 ± 3

89.3 ± 2.8

22.6 ± 0.7

8.9 ± 0.4

40.0 ± 2.5

41.9 ± 1.2

21.8 ± 0.6

54.0 ± 2.1

9.9 ± 0.6

7.37 ± 0.01

1.0 ± 0

117

480

116 ± 0

542 ± 68

Blo

od g

as p

aram

eter

(m

m H

g)

Figure 3 | Oxygen parameters in UA/UV lambs. Data from n¼ 8 lambs. (a) Haemodynamic and laboratory parameters. (b) Pre-membrane PaCO2 andPaO2. (c) Haemoglobin levels with and without erythropoietin (EPO). (d) Pre-membrane pH. (e) Plasma lactate. w In utero control values in (a) derived frommeasured data in ref. 18. Data in (b–e) are presented as mean±s.e.m. Statistically significant difference between groups in (c) denoted by *Po0.05(analysis of variance (ANOVA)).

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15112 ARTICLE

NATURE COMMUNICATIONS | 8:15112 | DOI: 10.1038/ncomms15112 |www.nature.com/naturecommunications 7


• Fysiologisch zuurstoftransport en -aanbod• Dagelijks erythropoiëtine (EPO) toediening• Normale groei en voortzetting orgaanrijping in plaats van ‘arrest’





Growth in UA/UV lambs

CCO (ml kg–1 min–1) 490 562 581

1 2 4 5 6 7

UA/UVControla

b c

In utero(micro-sphere)

GA 125d*

In utero(echo)

GA 109d

In utero(echo)

GA 135d8 Mean

±s.e.m.3†

(TOF)

586 666 760 503 467 635 603 699 594 ± 32‡

338 ± 13‡

256 ± 20‡

1.37 ± 0.06‡

196 ± 20

0.60 ± 0.06

22.3 ± 0.7

362

338

1.09

211

0.60

19.9

329

274

1.22

178

0.55

20.6

366

268

1.39

283

0.76

22.7

281

186

1.53

189

0.70

21.9

307

196

1.57

239

0.79

20.8

296

463

0.67

180

0.62

25.8

382

284

1.35

199

0.53

21.9

339

247

1.43

90

0.25

24.7

363

218

1.66

182

0.50

331

231

1.43

288

0.87

NA NA

321

169

1.90

289

0.90

1,000 1.0

0.5

0.0

500

00 350 700 105 125 145

Gestational age (days)

DA

flow

: RV

out

put r

atio

Time (h)

CC

O (

ml k

g–1 m

in–1

)

20.7

DA flow (ml kg–1 min–1)

RV output (ml kg–1 min–1)

LV output (ml kg–1 min–1)

RV:LV output ratio

DA flow: RV output ratio

Umbilical PaO2 (mm Hg)

Figure 4 | Echocardiographic parameters in UA/UV lambs. Data from n¼ 8 lambs. (a) Echocardiographic parameters. (b) Combined cardiac output.(c) Ductus arteriosus (DA) flow to right ventricular output ratio. Data in (b,c) are presented as mean±s.e.m. *In uteromicrosphere data in (a) derived frommeasured data in ref. 20. wLamb 3 noted to have Tetralogy of Fallot (TOF) with restricted pulmonary flow before cannulation was excluded from mean valuecalculations (z) due to TOF physiology.

Control

Mean±s.e.m.

Mean±s.e.m.

Inutero†

UA/UV no insulin UA/UV insulin

9

a

b c

Carbohydrate supplied (g kg–1 day–1)

Trophamine supplied (g kg–1 day–1)

Lipid supplied (g kg–1 day–1)

Growth (g kg–1 day–1)

Total calories supplied (kcal kg–1 day–1)

Plasma glucose (mg dl–1)

BUN (mg dl–1)

1 2 3 4 5 6 7 8

10.2

25

3.2

16

0.19

49.3

20.2

13.9 13.1 13.4 10.3 10.5

44

4.9

35

0.20

57.4

14.1

15.9 18.6 ± 2.7

29.5 ± 1.5

8.3 ± 0.6

22.5 ± 0.5

0.19 ± 0.01

98.2 ± 6.9

24.0 ± 3.8

13.6 ± 1.3

32 ± 2

6.0 ± 0.6

28 ± 2

0.20 ± 0.01

72.1 ± 6.6

21.7 ± 1.5

21.3

31

7.7

22

0.18

105.0

27.8

28

8.8

23

0.20

91.3

20.2

37

5.2

35

0.15

57.3

23.8

35

6.3

33

0.17

72.5

20.0

32

5.8

28

0.23

69.9

25.7

27

6.1

30

0.24

73.8

22.0

15

6

20

0

6

UA/UV no insulin (n=6)

ControlP = 0.09*

3

0100 125

Bod

y w

eigh

t (kg

)

6

3

0

Bod

y w

eigh

t (kg

)

y = 0.07359e0.02905x

r 2 = 0.88y = 0.1438e0.02311x

r 2 = 0.81

150


100 125 150


60

NA

Figure 5 | Nutrition and growth in UA/UV lambs. Data from n¼8 lambs. (a) Nutritional substrate and laboratory parameters; data are presented forindividual animals and as group averages (mean± s.e.m.). (b) Control growth curve using UA/UV and control lamb weights at hysterotomy (n¼ 19). Solidline represents exponential best fit. (c) UA/UVgrowth curve. Solid line represents exponential best fit of UA/UV non-insulin lamb weights at hysterotomyand at end of studies. Dashed line represents control growth curve. wIn utero control values in (a) derived from measured data in refs 36,37,59. *P value in(c) refers to between-group analysis of variance (ANOVA; statistical significance defined as Po0.05).

ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15112

8 NATURE COMMUNICATIONS | 8:15112 | DOI: 10.1038/ncomms15112 | www.nature.com/naturecommunications


EXTEND - EXTrauterine Environment for Neonatal Development 5 dagen support 28 dagen support


• Fysiologisch zuurstoftransport en -aanbod• Dagelijks erythropoiëtine (EPO) toediening• Normale groei en voortzetting orgaanrijping in plaats van ‘arrest’• Lammeren (GA 105-120 dagen) konden stabiel worden ondersteund

gedurende 20-28 dagen• Dagelijks echocardiografisch onderzoek: cardiac output in de fysiologische

range, nagenoeg normale foetale transductale en interatriale shunt flow





Transductale RtL-shunt



Antegrade flow ductus venosus Interatriale RtL-shunt

• Parenterale voeding via het extracorporele circuit (voornamelijk koolhydraten en eiwitten met slecht weinig vetten)

• Preventie van hyperglycaemie en hoog ureum (osmotische diurese en/of hyperosmolaliteit)

• Observatie van foetale ademhalingsbewegingen; correlatie met PaCO2 in systemische circulatie

• Openen van de ogen, steeds actiever worden, slikbewegingen• Toename in gewicht; groei van wolvacht



Partridge EA, Davey MG, Hornick MA, Flake AW. An EXTrauterine environment for neonatal development: EXTENDING fetal physiology beyond the womb. Semin Fetal Neonatal Med. 2017;22(6):404-9.




Objectieve verbetering van de longrijpheid

An additional disadvantage that has been raised is parentalperception of having their fetus in a ‘bag’. It is important toconsider that the comparator is the extreme premature infant ona ventilator and in an incubator. We feel that parents will berelatively reassured that their fetus is being maintained ina relatively protective and physiologic environment. The clinicaldevice will be designed with many features that should allow theparent to be connected with the fetus including ultrasound,

a darkfield camera allowing real-time visualization of the fetuswithin its darkened environment and the ability to play maternalheart and abdominal sounds to the fetus. We therefore feel thatthe advantages far outweigh the disadvantages of exposure of thefetus to the conventional care imposed on the critically preterminfant in the neonatal intensive care unit environment.

Finally, the umbilical cord offers the only physiologic vascularaccess for extracorporeal support for the fetus. The use of carotid

400a

b

c

d

e

k l

j

h i

f g

ControlEXTEND

200

Lung

vol

ume

(ml)

0

50

30

Tis

sue

fract

ion

(%)

10

Sur

face

den

sity

(cm

–1)

Sur

face

are

a (m

2 )

900

700

500

400P=0.78 *

200

0Control † UA/UV

mGA (days)

Publishedcontrol

(n=11)§UA/UV(n=5)

128

36±1

7.15±0.04

197±29

36±1100

437

3

63±5 35±4 35±143±3

21±15±0

7.45±0.02143±24

32±222±15±0

38±11

39±417±1

5.5±0.27.36±0.02

128±12

5.7±0.259±11

33±118±2

136±2

40

3

141±1

Near-termcontrol‡(n=3)

Resp rate (b.p.m.)PaCO2 (mm Hg)

PIP (cm H2O)

PEEP (cm H2O)pHPaO2 (mm Hg)

fiO2 (%)PIP (cm H2O)PEEP (cm H2O)A-a gr (mm Hg)

SP

-B p

ositi

ve (

cells

mm

–2)

30

Sep

tal t

hick

ness

(µm

) 18

14

10100 125

Gestational age (days)150

15

0

Figure 6 | Structural and biochemical lung development and early neonatal pulmonary function in UA/UV lambs. (a–e) Morphology of control ((f), 113dGA and (g),139d GA) and experimental lambs ((h), 132d GA, CA/UV lamb 3; (i), 144d GA, UA/UV lamb 5) following 19 and 28 days on circuit,respectively (scale bars, 50mm). Ongoing alveolar formation on circuit is evidenced by increased density and height of secondary septae (arrowheads).Density of surfactant protein-B-positive alveolar cells ((j), arrowheads in k,l) and neonatal pulmonary function were not different from that of age-matchedcontrols (m). *P value in (j) refers to difference between groups (Student’s unpaired t-test, statistical significance defined as Po0.05). wControl group in (j)includes near-term lambs only (n¼4, mean GA 141 days). yMean control values in (m) derived from measured data in ref. 24. zNear-term control lambsin (m) delivered by caesarean section and ventilated in the same manner as experimental animals. Data in (j,m) are presented as mean±s.e.m.



UA/UV lambs(19 & 28d support)

Controls

GA 113d GA 139d

GA 132d GA 144d






400a

b

c

d

e

k l

j

h i

f g

ControlEXTEND

200

Lung

vol

ume

(ml)

0

50

30

Tis

sue

fract

ion

(%)

10

Sur

face

den

sity

(cm

–1)

Sur

face

are

a (m

2 )

900

700

500

400P=0.78 *

200

0Control † UA/UV

mGA (days)

Publishedcontrol

(n=11)§UA/UV(n=5)

128

36±1

7.15±0.04

197±29

36±1100

437

3

63±5 35±4 35±143±3

21±15±0

7.45±0.02143±24

32±222±15±0

38±11

39±417±1

5.5±0.27.36±0.02128±12

5.7±0.259±11

33±118±2

136±2

40

3

141±1



PIP (cm H2O)



SP

-B p

ositi

ve (

cells

mm

–2)

30

Sep

tal t

hick

ness

(µm

) 18

14

10100 125


15

0







400a

b

c

d

e

k l

j

h i

f g

ControlEXTEND

200

Lung

vol

ume

(ml)

0

50

30

Tis

sue

fract

ion

(%)

10

Sur

face

den

sity

(cm

–1)

Sur

face

are

a (m

2 )

900

700

500

400P=0.78 *

200

0Control † UA/UV

mGA (days)

Publishedcontrol

(n=11)§UA/UV(n=5)

128

36±1

7.15±0.04

197±29

36±1100

437

3

63±5 35±4 35±143±3

21±15±0

7.45±0.02143±24

32±222±15±0

38±11

39±417±1

5.5±0.27.36±0.02128±12

5.7±0.259±11

33±118±2

136±2

40

3

141±1



PIP (cm H2O)



SP

-B p

ositi

ve (

cells

mm

–2)

30

Sep

tal t

hick

ness

(µm

) 18

14

10100 125


15

0







400a

b

c

d

e

k l

j

h i

f g

ControlEXTEND

200

Lung

vol

ume

(ml)

0

50

30

Tis

sue

fract

ion

(%)

10

Sur

face

den

sity

(cm

–1)

Sur

face

are

a (m

2 )

900

700

500

400P=0.78 *

200

0Control † UA/UV

mGA (days)

Publishedcontrol

(n=11)§UA/UV(n=5)

128

36±1

7.15±0.04

197±29

36±1100

437

3

63±5 35±4 35±143±3

21±15±0

7.45±0.02143±24

32±222±15±0

38±11

39±417±1

5.5±0.27.36±0.02128±12

5.7±0.259±11

33±118±2

136±2

40

3

141±1



PIP (cm H2O)



SP

-B p

ositi

ve (

cells

mm

–2)

30

Sep

tal t

hick

ness

(µm

) 18

14

10100 125


15

0




Objectieve verbetering van de longfunctie



nondirective counselling before the procedure. The ability toplace an infant on the system after vaginal delivery, or to clearcontamination under that circumstance, or circumstances ofchorioamnionitis, remain to be experimentally determined, butwould remain a possibility if umbilical vascular spasm can beprevented or reversed and contamination can be contained and/or fetal infection treated.

The initial clinical target population for this therapy will likelybe the 23–25-week extreme premature infant. At the present timethe morbidity and mortality of this population would seem tojustify general application of this technology if it were provento dramatically improve outcomes in clinical trials. Futuredevelopments may allow better prediction of those infants whoare destined for extreme premature delivery55 and may allowgenetic prediction of infants who are most at risk for mortalityand morbidity if born premature56,57. This would in turnallow risk stratification of potential patients and improvedselection of patients who would be most likely to benefit.An important point is that placement on the system wouldnot be prohibitive to standard therapies for extreme prematureinfants. For instance, prenatal glucocorticoids could still beadministered, and rapid delivery from the system and conversionto standard premature neonatal care would be necessary andwarranted if the system failed. Before 22–23 weeks of gestation,

there are likely physiologic and technical limitations that willincrease the risk and reduce the potential benefit of this therapy.Our goal is not to extend the current limits of viability, but ratherto offer the potential for improved outcomes for those infantswho are already being routinely resuscitated and cared for inneonatal intensive care units. Finally, the implications of thistechnology extend beyond clinical application to extremepremature infants. Potential therapeutic applications mayinclude treatment of fetal growth retardation related toplacental insufficiency or the salvage of preterm infantsthreatening to deliver after fetal intervention or fetal surgery.The technology may also provide the opportunity to deliverinfants affected by congenital malformations of the heart, lungand diaphragm for early correction or therapy before theinstitution of gas ventilation. Numerous applications related tofetal pharmacologic, stem cell or gene therapy could be facilitatedby removing the possibility for maternal exposure and enablingdirect delivery of therapeutic agents to the isolated fetus. Finally,our system offers an intriguing experimental model foraddressing fundamental questions regarding the role of themother and placenta in fetal development. Long-term physiologicmaintenance of a fetus amputated from the maternal–placentalaxis has now been achieved, making it possible to study therelative contribution of this organ to fetal maturation.

Per

cent

bod

y w

eigh

t (%

)

Gyr

al w

idth

(m

m)

2.0

a b

c

d

6

4

2

0

Ctrl.

Exp.

P > 0.05 for all regionsP ≥ 0.43 for all regions

P ≥ 0.40 for all time points

1.5

1.0

0.5

0.0

Bip

arie

tal d

iam

eter

(m

m)

56

54

52

50

48

46

440 5 10 15

Predicted BPD = (log(EFW)–1.2)/0.044

Time on circuit (days)20

Predicted

Exp.

25

Cereb

rum

Cereb

ellum

Total

brain

R fron

tal

L fro

ntal

R parie

tal

L par

ietal

Figure 7 | Neurologic development and maturation in experimental lambs. (a) Post-mortem brain-to-body weight ratio of experimental (Exp.) andcontrol (Ctrl.) animals; animals that received insulin are excluded. (b) Gyral width on haematoxylin and eosin (H&E) stained sections by region ascompared with 140-day gestation controls. (c) Biparietal diameter in experimental (Exp.) versus predicted (equation derived from ref. 26) animals.(d) Postnatal T2-weighted coronal magnetic resonance imaging (MRI) at 6 months of age. Scale bar in (d) is 1 cm. Data in (a–c) are presented asmean±s.e.m. P values in (a–c) refer to difference between control and experimental groups (Student’s t-test for each region/time point, with statisticalsignificance defined as Po0.05). BPD, bronchopulmonary dysplasia.



Normale opbouw, gewicht van de hersenen zonder aanwijzingen voor bloedingen of infarceringen

Ethische vraagstukken

placental pathology such as maternal vascular under perfu-sion, such as occurs with preeclampsia and fetal growth re-striction, both of which are associated with increased risk ofBPD.10

Environmental ExposuresMultiple environmental exposures can directly or indirectlyaffect lung development at any gestational age, but preterminfants may be particularly vulnerable. Epigenetic changes con-sisting of DNA methylation, histone modifications, andmicroRNA changes in response to a variety of environmen-tal stimuli such as toxins, oxidative stress, and infection mayincrease BPD susceptibility by altering the expression of genesinvolved in prenatal and postnatal lung development.2 For in-stance, a recent study identified multiple genes potentially regu-lated by DNA methylation during normal alveolar septationin the mouse and human lung, and in BPD.11 In utero smokeexposure modifies the methylation of specific genes, has beenassociated with changes in indices of global DNA methyla-tion, and biologic pathways impacted through epigeneticchanges by in utero smoke are being identified.12 Maternal pre-natal stress, cortisol, in utero smoke, particulate exposure, andobesity have been shown to be independently associated withchild wheeze, likely through programming mechanisms. Lon-gitudinal samples from patients at risk for BPD are needed toexamine longitudinal methylome and transcriptome changes.

Inflammation and Host Immune ResponsesPrenatal inflammation is strongly associated with an in-creased risk for BPD.13 Better understanding of the role of lung

inflammation and host immune responses in BPD pathobiologyshould facilitate development of inflammatory biomarker panelsfor BPD prediction and intervention targets. Selective anti-inflammatory therapies and modulators of innate immunityat the maternal-fetal interface and its impact on the subse-quent lung microbiome of the preterm infants at risk for BPDneed to be further defined.

Postnatal Interventions

Respiratory Support at Birth and Strategies toReduce Ventilator Associated InjuryMost extremely low birth weight (ELBW) infants require re-spiratory support at birth. Animal studies have demon-strated that even a brief exposure to large tidal volumes at birthmay cause significant lung injury predisposing to BPD.9 Becauseinvasive respiratory support is a major contributor to the de-velopment of BPD, application of noninvasive respiratorysupport has become a popular strategy in its prevention. Arecent meta-analysis showed a significant decrease in the in-cidence of BPD or death (OR 0.83; CI 0.71-0.96) with earlynasal continuous positive airway pressure (NCPAP) vs me-chanical ventilation.14 Studies have evaluated nasal ventila-tion (nasal intermittent positive pressure ventilation) as analternative to NCPAP or intubation, but a large randomizedcontrolled trial (RCT) did not show superiority of this ap-proach in reducing death or BPD compared with NCPAP (OR1.09; CI 0.83-1.43, P = 0.56).15

RCTs of approaches to minimize ventilator associated lunginjury, including high frequency oscillatory ventilation and

Figure. Windows of opportunities for prevention of BPD. Antenatal and postnatal factors can predispose the structurally andbiochemically immature lung to the development of BPD. BPD most commonly occurs in extremely low gestational age new-borns born during the canalicular or early saccular phases of lung development. However, not all extremely premature infantsdevelop BPD, suggesting BPD can be prevented. Figure identifies potential windows of opportunity for primary prevention ofBPD. IUGR, intrauterine growth retardation. Reprinted with permission of the American Thoracic Society. Copyright © 2017American Thoracic Society. McEvoy CT, Jain L, Schmidt B, Abman S, Bancalari E, Aschner JL. NHLBI Workshop on the primaryprevention of chronic lung disease: Bronchopulmonary dysplasia. Ann Am Thorac Soc 2014; 11: S146-S153.

Volume 189 • October 2017

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Aanvullende vragen• Invloed op hechting en binding moeder/ouders• Juridische aspecten• Afweging risico’s versus voordelen• Grens van levensvatbaarheid

Artificial womb

• UMC’s• TU’s• Overheidsinstanties• Bedrijven

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