Study protocol: developing, disseminating, and implementing a core outcome set for selective fetal growth restriction in monochorionic twin pregnancies.

BACKGROUND: Selective fetal growth restriction in monochorionic twin pregnancies is associated with an increased risk of perinatal mortality and morbidity and represents a clinical dilemma. Interventions include expectant management with early preterm delivery if there are signs of fetal compromise, selective termination of the compromised twin, fetoscopic laser coagulation of the communicating placental vessels or termination of the whole pregnancy. Previous studies evaluating interventions have reported many different outcomes and outcome measures. Such variation makes comparing, contrasting, and combining results challenging, limiting ongoing research on this uncommon condition to inform clinical practice. We aim to produce, disseminate, and implement a core outcome set for selective fetal growth restriction research in monochorionic twin pregnancies. METHODS: An international steering group, including professionals, researchers, and lay experts, has been established to oversee the development of this core outcome set. The methods have been guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. Potential core outcomes will be developed by undertaking a systematic review of studies evaluating interventions for selective fetal growth restriction in monochorionic twin pregnancies. Potential core outcomes will be entered into a three-round Delphi survey and key stakeholders including clinical professionals, researchers, and lay experts will be invited to participate. Repeated reflection and rescoring of individual outcomes should encourage group and individual stakeholder convergence towards consensus outcomes which will be entered into a modified Nominal Group Technique to finalize the core outcome set. Once core outcomes have been agreed, we will establish standardized definitions and recommend high-quality measurement instruments for each outcome. DISCUSSION: The development, dissemination, and implementation of a core outcome set for selective fetal growth restriction should ensure that future research protocols select, collect, and report outcomes and outcome measures in a standardized manner. Data synthesis will be possible on a broad level and rigorous implementation should advance the quality of research studies and their effective use in order to guide clinical practice, improve patient care, maternal, short-term perinatal outcomes, and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) registration number: 998. International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018092697 . 18th April 2018.

Construction and comparative analyses of highly dense linkage maps of two sweet cherry intra-specific progenies of commercial cultivars.

Despite the agronomical importance and high synteny with other Prunus species, breeding improvements for cherry have been slow compared to other temperate fruits, such as apple or peach. However, the recent release of the peach genome v1.0 by the International Peach Genome Initiative and the sequencing of cherry accessions to identify Single Nucleotide Polymorphisms (SNPs) provide an excellent basis for the advancement of cherry genetic and genomic studies. The availability of dense genetic linkage maps in phenotyped segregating progenies would be a valuable tool for breeders and geneticists. Using two sweet cherry (Prunus avium L.) intra-specific progenies derived from crosses between 'Black Tartarian' × 'Kordia' (BT×K) and 'Regina' × 'Lapins'(R×L), high-density genetic maps of the four parental lines and the two segregating populations were constructed. For BT×K and R×L, 89 and 121 F(1) plants were used for linkage mapping, respectively. A total of 5,696 SNP markers were tested in each progeny. As a result of these analyses, 723 and 687 markers were mapped into eight linkage groups (LGs) in BT×K and R×L, respectively. The resulting maps spanned 752.9 and 639.9 cM with an average distance of 1.1 and 0.9 cM between adjacent markers in BT×K and R×L, respectively. The maps displayed high synteny and co-linearity between each other, with the Prunus bin map, and with the peach genome v1.0 for all eight LGs (LG1-LG8). These maps provide a useful tool for investigating traits of interest in sweet cherry and represent a qualitative advance in the understanding of the cherry genome and its synteny with other members of the Rosaceae family.

Results of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia and the set up of the randomized controlled TOTAL trial.

In isolated congenital diaphragmatic hernia, lung size and/or the position of the liver are predictive of neonatal outcome. Percutaneous Fetal Endoscopic Tracheal Occlusion (FETO) by a balloon can be undertaken to prompt lung growth in the worst cases. The feasibility and safety of FETO is no longer at stake, and it is associated with an apparent increase in neonatal survival. The gestational age at birth, the pre-existing lung size, the ability to remove the balloon prior to birth, and the lung response are predicting outcome. The most frequent complication is preterm premature rupture of the membranes, and as a consequence preterm delivery, which also complicates balloon removal. We have set up a randomized trial for the formal evaluation of FETO in Europe, including criteria for fetoscopy centers. Training of European as well as North American centers is taking place, so that the procedure could be safely and more widely offered.

Changing perspectives on the perinatal management of isolated congenital diaphragmatic hernia in Europe.

Congenital diaphragmatic hernia (CDH) should be diagnosed in the prenatal period and prompt referral to a tertiary referral center for imaging, genetic testing, and multidisciplinary counseling. Individual prediction of prognosis is based on the absence of additional anomalies, lung size, and liver herniation. In severe cases, a prenatal endotracheal balloon procedure is currently being offered at specialized centers. Fetal intervention is now also offered to milder cases within a trial, hypothesizing that this may reduce the occurrence of bronchopulmonary dysplasia in survivors. Postnatal management has been standardized by European high-volume centers for the purpose of this and other trials.

Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26-28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre-existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design.

The role of ultrasound examination in the first trimester and at 16 weeks' gestation to predict fetal complications in monochorionic diamniotic twin pregnancies.

OBJECTIVE: The purpose of this study was to determine the value of ultrasound examination in the first trimester and at 16 weeks to predict fetal complications in monochorionic diamniotic (MCDA) twin pregnancies, defined as the occurrence of either twin-to-twin transfusion syndrome, severe discordant growth, or intrauterine death. STUDY DESIGN: We identified risk factors to predict a complicated fetal outcome in the first trimester and at 16 weeks in a prospective cohort of 202 twin pregnancies recruited during the first trimester in 2 centers of the EuroTwin2Twin project. RESULTS: Significant predictors in the first trimester were the difference in crown-rump length (odds ratio [OR], 11) and discordant amniotic fluid (OR, 10). At 16 weeks, significant predictors were the difference in abdominal circumference (OR, 29), discordant amniotic fluid (OR, 7), and discordant cord insertions (OR, 3). Risk assessment in the first trimester and at 16 weeks detected 29% and 48% of cases with a complicated fetal outcome, respectively, with a false-positive rate of 3% and 6%, respectively. Combined first-trimester and 16 week assessment identified 58% of fetal complications, with a false-positive rate of 8%. CONCLUSION: Of the MCDA twin pregnancies classified as high risk on the combined first trimester and 16 weeks assessment (n = 41), 73% had a complicated fetal outcome with a survival rate of only 69%. In contrast, of the pregnancies classified as low risk (n = 154), 86% had an uneventful fetal outcome with a survival rate of 95%.

Clinical outcome and placental characteristics of monochorionic diamniotic twin pairs with early- and late-onset discordant growth.

OBJECTIVE: The purpose of this study was to examine the clinical and placental characteristics of monochorionic diamniotic twin pregnancies with early-onset discordant growth diagnosed at 20 weeks, late-onset discordant growth diagnosed at 26 weeks or later, and concordant growth. STUDY DESIGN: We studied a prospective cohort that underwent an ultrasound scan in the first trimester, at 16, 20, and 26 weeks. We excluded pregnancies complicated by twin-to-twin transfusion syndrome, miscarriage, fetal death less than 16 weeks, or severe congenital anomalies. Placental sharing and angioarchitecture were assessed by injection of each cord vessel with dyed barium sulphate. The 2 territories were delineated on an X-ray angiogram. The diameter of each intertwin anastomosis was measured on a digital photograph. RESULTS: We included 178 twin pairs. Early onset discordant growth, late-onset discordant growth, and concordant growth occurred in 15, 13, and 150 pregnancies, respectively. Twin pairs with early-onset discordant growth had lower survival rates and were delivered at an earlier gestational age than pairs with late-onset discordant and concordant growth. The degree of birthweight discordance was similar in early- and late-onset discordant growth. Severe intertwin hemoglobin differences at the time of birth occurred in 0%, 38%, and 3% of pairs with early-onset discordant growth, late-onset discordant growth, and concordant growth, respectively. The placentas of pairs with early-onset discordant growth were more unequally shared and had larger arterioarterial anastomoses and a larger total anastomotic diameter as compared with placentas of pairs with late onset-discordant or concordant growth. CONCLUSION: Unequal placental sharing appears to be involved in the etiology of early-onset discordant growth, whereas a late intertwin transfusion imbalance may be involved in some cases with late-onset discordant growth.

The outcome of monochorionic diamniotic twin gestations in the era of invasive fetal therapy: a prospective cohort study.

OBJECTIVE: The purpose of this study was to document pregnancy and neonatal outcome of monochorionic diamniotic twin pregnancies. STUDY DESIGN: This observational study describes a prospective series included in the first trimester in 2 centers of the Eurotwin2twin project. RESULTS: Of the 202 included twin pairs, 172 (85%) resulted in 2 survivors, 15 (7.5%) in 1 survivor, and 15 (7.5%) in no survivors. The mortality was 45 of 404 (11%), and 36 of 45 (80%) were fetal losses of 24 weeks or less, 5 of 45 (11%) between 24 weeks and birth, and 4 of 45 (9%) were neonatal deaths. Twin-to-twin transfusion syndrome (TTTS) occurred in 18 of 202 (9%). The mortality of TTTS was 20 of 36 (55%), which accounted for 20 of 45 (44%) of all losses. Severe discordant growth without TTTS occurred in 29 of 202 (14%). Its mortality was 5 of 58 (9%), which accounted for 5 of 45 (11%) of all losses. Major discordant congenital anomalies occurred in 12 of 202 (6%). Of the 178 pairs that continued after 24 weeks, 10 (6%) had severe hemoglobin differences at birth. After 32 weeks, the prospective risk of intrauterine demise was 2 in 161 pregnancies (1.2%; 95% confidence interval, 0.3-4.6). CONCLUSION: Of the monochorionic twins recruited in the first trimester, 85% resulted in the survival of both twins, and 92.5% resulted in the survival of at least 1 twin. Most losses were at 24 weeks or less, and TTTS was the most important cause of death. After 32 weeks, the risk of intrauterine demise appears to be small.

Prediction of outcome in isolated congenital diaphragmatic hernia and its consequences for fetal therapy.

Congenital diaphragmatic hernia (CDH) can be diagnosed in the prenatal period either as part of other anomalies or as an isolated birth defect. The clinical impact of this surgically correctable anatomical defect lies in its impairment of lung development. Currently, up to 30% of babies with isolated CDH die from the consequences of lung hypoplasia and/or pulmonary hypertension. Antenatal prediction of outcome essentially relies on the measurement of lung development by the so-called lung area to head circumference ratio (LHR). By expressing observed LHR as a proportion of what is normally expected (O/E LHR) at a certain time point in gestation, a prediction of outcome can be made. When O/E LHR is less than 25% of the normal, postnatal death is very likely. In these cases, an antenatal intervention that can improve lung development is currently offered. Currently, this is done by percutaneous fetal endoscopic tracheal occlusion (FETO) with a balloon at 26-28 weeks, and reversal of occlusion at 34 weeks. The feasibility and safety of percutaneous FETO have been established and the procedure seems to improve outcome in severe CDH. The lung response to, and outcome after, FETO depend on pre-existing lung size respectively gestational age at birth. Prenatal decision making can therefore be stratified according to measured lung size.

Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO).

OBJECTIVE: The objective of the study was to investigate the value of fetal lung area to head circumference ratio in the prediction of the postnatal outcome in left-sided congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion. STUDY DESIGN: The lung area to head circumference ratio was measured before fetoscopic endoluminal tracheal occlusion in 28 fetuses with congenital diaphragmatic hernia at 25 to 29 weeks. Regression analysis was used to investigate the effect on survival of lung area to head circumference ratio, gestation at fetoscopic endoluminal tracheal occlusion, gestation at delivery, preterm amniorrhexis following fetoscopic endoluminal tracheal occlusion, and prenatal removal of the balloon. RESULTS: The median lung area to head circumference ratio prior to fetoscopic endoluminal tracheal occlusion was 0.7 (range 0.5 to 0.9). The median gestation at delivery was 34 (range 27 to 39) weeks, and there were 16 survivors (57%). Only lung area to head circumference ratio provided significant prediction of survival, which increased from 17% for lung area to head circumference ratio of 0.4 to 0.5 to 62% for lung area to head circumference ratio of 0.6 to 0.7 and 78% for lung area to head circumference ratio of 0.8 to 0.9. CONCLUSION: In congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion, postnatal survival can be predicted by the lung area to head circumference ratio measured prior to the procedure.

Prenatal intervention for isolated congenital diaphragmatic hernia.

PURPOSE OF REVIEW: We aim to review the recent literature regarding early prenatal prediction of outcome in babies diagnosed with isolated congenital diaphragmatic hernia, as well as results of fetal therapy for this condition. RECENT FINDINGS: Current survival rates in population-based studies are around 55-70%. Highly specialized centers report 80% and more, but discount the hidden mortality, mainly in the antenatal period. Fetuses presenting with liver herniation and a lung-to-head ratio of less than 1.0 measured in midgestation have a poor prognosis. Other volumetric techniques are being evaluated for use in midtrimester. Recently, a randomized trial failed to show benefit from prenatal therapy, but lacked power to document the potential advantage of prenatal therapy in severe cases. We proposed percutaneous fetal endoluminal tracheal occlusion with a balloon at 26-28 weeks through a 3.3 mm incision. In severe cases, fetal endoluminal tracheal occlusion increased lung size as well as survival, with an early (7 day) survival, late neonatal (28 day) survival and survival at discharge of 75, 58 and 50%, respectively, comparing favorably with 9% in contemporary controls. Airways can be restored prior to birth improving neonatal survival (83.3% compared with 33.3%). The procedure carries a risk for preterm prelabour rupture of the fetal membranes, although that may decrease with experience. SUMMARY: Fetuses with severe congenital diaphragmatic hernia can be identified in the second trimester. Fetal endoluminal tracheal occlusion can be considered as a minimally invasive fetal therapy, improving outcome in such highly selected cases.

Prenatal intervention for isolated congenital diaphragmatic hernia.

PURPOSE OF REVIEW: We aim to review the recent literature regarding early prenatal prediction of outcome in babies diagnosed with isolated congenital diaphragmatic hernia, as well as results of fetal therapy for this condition. RECENT FINDINGS: Current survival rates in population-based studies are around 55-70%. Highly specialized centers report 80% and more, but discount the hidden mortality, mainly in the antenatal period. Fetuses presenting with liver herniation and a lung-to-head ratio of less than 1.0 measured in midgestation have a poor prognosis. Other volumetric techniques are being evaluated for use in midtrimester. Recently, a randomized trial failed to show benefit from prenatal therapy, but lacked power to document the potential advantage of prenatal therapy in severe cases. We proposed percutaneous fetal endoluminal tracheal occlusion with a balloon at 26-28 weeks through a 3.3 mm incision. In severe cases, fetal endoluminal tracheal occlusion increased lung size as well as survival, with an early (7 day) survival, late neonatal (28 day) survival and survival at discharge of 75, 58 and 50%, respectively, comparing favorably with 9% in contemporary controls. Airways can be restored prior to birth improving neonatal survival (83.3% compared with 33.3%). The procedure carries a risk for preterm prelabour rupture of the fetal membranes, although that may decrease with experience. SUMMARY: Fetuses with severe congenital diaphragmatic hernia can be identified in the second trimester. Fetal endoluminal tracheal occlusion can be considered as a minimally invasive fetal therapy, improving outcome in such highly selected cases.

Pregnancy and infant outcome of 80 consecutive cord coagulations in complicated monochorionic multiple pregnancies.

OBJECTIVE: This study was undertaken to document pregnancy and infant outcome after cord coagulation with laser and/or bipolar as a technique for selective feticide in complicated monochorionic multiple pregnancies. STUDY DESIGN: Prospective follow-up study in 2 tertiary fetal medicine centers. RESULTS: Eighty cases were included in the study (73 twins, 7 triplets). The survival rate was 83% (72/87). There were 9 intrauterine fetal deaths (10%), 5 within 24 hours and 4 between 4 and 10 weeks after the procedure. There was 1 termination of pregnancy because of chorioamnionitis. Median gestational age at delivery was 35.4 weeks, with 79% of patients delivering after 32 weeks. Preterm prelabor rupture of the membranes before 25 weeks accounted for all perinatal deaths (n = 5). Of the children older than 1 year of age (n = 67), 62 (92%) have a normal development. CONCLUSION: Cord coagulation is an effective method for selective feticide in monochorionic multiple pregnancies.

Intertwin anastomoses in monochorionic placentas after fetoscopic laser coagulation for twin-to-twin transfusion syndrome: is there more than meets the eye?

OBJECTIVE: This study was undertaken to detect missed anastomoses on the chorionic surface as well as hidden connections in the depth of the cotyledons in placentas after laser coagulation for twin-to-twin transfusion syndrome (TTTS) and to correlate these findings to clinical outcome. STUDY DESIGN: All cord vessels were injected with dyed barium sulphate. A digital photograph of the chorionic surface angioarchitecture and single-shot digital X-ray (Rx) angiograms were made. The presence and diameter of any missed anastomoses on the chorionic surface and of any hidden angiographic connections were determined. RESULTS: Fifty placentas were analyzed, 7 of double intrauterine fetal death (IUFD) and 43 of double survivors. In 9 of 43 (21%) cases with double survival and in all 7 cases of double IUFD, missed anastomoses were identified that should have been ablated by laser coagulation (P < .001). There appeared to be a correlation between the type and diameter of missed anastomoses on the chorionic surface and the clinical outcome. Placentas with missed large arteriovenous/venoarterial anastomoses (AV/VA) (N = 8) were from cases with recurrent TTTS or double IUFD (unless compensated by a large arterioarterial anastomosis [AA]). Next, missed small AV/VA (N = 4) without AA resulted in isolated (ie, without TTTS) discordant hemoglobin levels requiring intrauterine transfusion. Finally, when there were no missed anastomoses (N = 34), TTTS had resolved in all cases and outcome was good, although 1 case had discordant hemoglobin values treated with a single intrauterine transfusion and 4 others had discordant hemoglobin at birth. On Rx angiography, potential hidden connections were present, all but 1 case. CONCLUSION: Coagulation of all anastomoses visible on the chorionic surface seems adequate to treat TTTS. However, hidden connections in the depth of the cotyledon could not be excluded and may be involved in lesser degrees of intertwin transfusion.

Current consequences of prenatal diagnosis of congenital diaphragmatic hernia.

BACKGROUND: Today, the diagnosis of congenital diaphragmatic hernia (CDH) can readily be made in the prenatal period during screening ultrasound examination. Patients ought to be referred to rule out associated anomalies, and in isolated cases, prognosis is poor when the liver is intrathoracic and the lung-to-head ratio (LHR) is less than 1. In these patients, prenatal intervention aiming to reverse pulmonary hypoplasia can be considered. METHODS: We present our current algorithm for counselling patients presenting with CDH. Patients with a poor prognosis are offered percutaneous fetal endoluminal tracheal occlusion (FETO) with a balloon, inserted at 26 to 28 weeks. We report on the evolution of technique and results in a consecutive homogeneous case series and compare outcome in cases with similar severity managed in the postnatal period. RESULTS: Within a period of 28 months, FETO was performed between 26 and 28 weeks in 24 fetuses with severe left-sided CDH. Under general (n = 5), epidural (n = 17) or local (n = 2) anesthesia, the balloon was successfully positioned at first surgery (23/24) with a mean operation time of 20 minutes (range, 3-60 minutes). There were no serious maternal complications or direct fetal adverse effects. In the first 2 weeks after FETO, LHR increased from 0.7 to 1.7. Premature prelabour rupture of the membrane (PPROM) occurred in 16.7% and 33.3% at 28 and 32 weeks or earlier, respectively. Gestational age at delivery was 33.5 weeks. Patency of airways was restored either in the prenatal (n = 12) or perinatal period (n = 12). Early (7 days) and late (28 days) survival, and survival at discharge were 75% (18/24), 58.3% (14/24) and 50% (12/24), respectively. Half of nonsurvivors (n = 6) died of pulmonary hypoplasia and hypertension, in combination with PPROM and preterm delivery (n = 4) and balloon dislodgement (n = 2), which coincided with a short tracheal occlusion (TO) period (12 days). In the other 6, TO period was comparable to that in the 12 survivors (47 vs 42 days, respectively). In that group of 6 babies, only 2 died of pulmonary problems. Late neonatal survival (28 days) was higher with prenatal vs perinatal balloon retrieval 83.3% vs 33.3% (P = .013). In a multicentre study validating the criteria, survival till discharge in 37 comparable cases was 9% (3/32) and 13% (5/37) of parents opted for termination. CONCLUSION: Fetuses with isolated left-sided CDH, liver herniation, and LHR of less than 1 have a poor prognosis. Percutaneous FETO is minimally invasive and may improve the outcome in these highly selected cases. Airways can be restored before birth, allowing vaginal delivery and return to the referring tertiary unit and may improve survival rate. The procedure carries a risk for PPROM, although that may decrease with experience.

Fetal intervention for congenital diaphragmatic hernia: the European experience.

Fetuses with CDH presenting with liver herniation and a lung area-to-head circumference ratio of less than 1.0 have a high chance for neonatal death due to pulmonary hypoplasia. Fetal tracheal occlusion (TO) prevents egress of lung liquid, which triggers lung growth. In animal experiments, we were able to develop a minimally invasive technique for Fetoscopic Endoluminal Tracheal Occlusion (FETO) with a detachable balloon. In 2001, we demonstrated feasibility of FETO by percutaneous access in fetuses with severe CDH. In a retrospective multicenter review, we obtained LHR measurements and position of the liver in 134 cases of isolated left-sided CDH between 24 and 28 weeks. Eleven patients (8%) with LHR < 1.4 opted for termination. Overall survival of liveborn babies was 47% (58/123). LHR and position of the liver correlated both to survival. Combination of both variables predicted neonatal outcome better: liver up and LHR < 1.0 predicted a survival of 9%. When LHR < 0.6, there were no survivors irrespective of liver position. We could successfully perform endotracheal placement of the balloon in 20 cases at a median gestational age of 26 weeks. The mean duration of the operation was 22 (range 5-54) minutes. In 11 (55%) of these patients, there was postoperative prelabor (ie, <37 weeks) amniorrhexis. Membranes ruptured before 32 weeks in 35%, with a decreasing trend as experience increased. Ultrasound scans after FETO demonstrated an increase in the echogenicity of the lungs within 48 hours and improvement in the LHR from a median 0.7 (range 0.4-0.9) before FETO to 1.8 (range 1.1-2.9) within 2 weeks after surgery. The median gestation at delivery was 33.2 (range 27-38) weeks, and in 14 (70%) this occurred after 32 weeks. Surgical repair of the diaphragmatic hernia could be done in 13 babies, and in all but 1 the defect was extensive and required the insertion of a patch. Survival to discharge was 50%. These 10 long-term surviving babies are now aged 7 to 26 (median 19) months without known neurologic morbidity. Eight babies died in the neonatal period due to complications of the underlying disease. Two nonsurvivors died from other causes but with appropriately developed lungs. Improved survival coincided with increasing experience, in turn related to reduced incidence of postoperative amniorrhexis, later delivery, and a change in the policy on the timing of removal of the balloon from intrapartum to the prenatal period. Survival in eligible contemporary controls was 1/12 (8%). The presence of liver herniation and a low lung-to-head ratio (LHR <1.0) is a good predictor of poor prognosis at different tertiary centers around the world. Severe CDH may be successfully treated with FETO, which is minimally invasive and may improve postnatal survival.

Pulmonary effects of in utero tracheal occlusion are dependent on gestational age in a rabbit model of diaphragmatic hernia.

PURPOSE: The authors investigated the effect of gestational age on lung development and maturation after in utero tracheal occlusion (TO) in a rabbit model of congenital diaphragmatic hernia (CDH). METHODS: In 46 fetal rabbits, CDH was created at 23 days' gestational age (GA; term, 31 days), corresponding to the pseudoglandular phase of lung development. A second intervention was performed at either 26, 27, or 28 days on 6 fetuses in each GA group. At that time, either TO (CDH + TO), or a sham operation (CDH + sham) was performed. Nonoperated littermates served as internal normal controls (CTR). All fetuses were delivered by cesarean section at 30 days GA to assess lung response by lung-to-body-weight ratio, pulmonary morphometry, and the density of type II pneumocytes. RESULTS: After TO, the lungs were significantly larger than in CDH animals; their weight was proportional to the duration of TO. Pulmonary morphometry in TO fetuses was comparable with that of controls. The density of type II cells was inversely related to the gestational age at which TO was performed, with normal values with TO at GA at 28 days. CONCLUSION: Timing of TO is critical to subsequent pulmonary development: early in gestation TO leads to pulmonary overgrowth and type II pneumocyte depletion, whereas normal values are obtained when TO is delayed till 28 of 32 days.

Ex vivo testing of a temperature- and pressure-controlled amnio-irrigator for fetoscopic surgery.

BACKGROUND: Currently, amnioinfusion fluids used in operative fetoscopy usually are preheated to body temperature. As the complexity of procedures increases, purposed designed devices should be designed that allow control of pressure and temperature during amnioinfusion or amnioexchange. In the current study, a prototype amnio-irrigator and fluid heater were evaluated. METHODS: The medical fluid heater heats fluid by conduction up to 37 degrees C. The maximum irrigation pressure and flow rates can be preset. Actual irrigation pressure (0 to 30 mm Hg) and flow rate (0 to 300 mL/min) can be read on the front panel. A series of ex vivo experiments were set up to determine the relationship between the flow rate (FR) and lumen of the instruments as well as the maximum flow rate (MFR) with and without the pressure control. Further, the relationship between FR and the irrigation pressure (IP) was determined. In an artificial pseudoamniotic sac the relationship between FR and change in temperature was measured, with and without the use of the medical fluid heater. RESULTS: When the IP was limited to 24 mm Hg, FR and pressure were correlated (r = 0.34; P <.001). The larger the functional lumen of the fetoscopic instrumentation, the higher the flow (r = 0.43; P <.001) and the lower the increase in IP (r = -0.47; P <.001). A quadratic relation between flow and temperature was observed both for preheated fluid as when using the fluid heater (r(2) = 0.71 and r(2) = 0.88; P <.001). However, at low flow rates, a thermal decrease of over 3 degrees C was observed when the fluid heater was not used. CONCLUSIONS: The current study quantifies an expected relationship between the diameter of the irrigation channel and achievable flow rates. It also shows that a medical fluid heater is needed when strict control of temperature would be desired.