Publications by authors named "Francesca Maria Russo"

22 Publications

  • Page 1 of 1

The outcomes of monoamniotic twin pregnancies from the first trimester onward.

Fetal Diagn Ther 2022 Jul 26. Epub 2022 Jul 26.

Introduction: Monochorionic monoamniotic (MCMA) twins are rare, and information is lacking on pregnancy outcomes from the first trimester onward. This study compares the pregnancy and neonatal outcomes between MCMA and monochorionic diamniotic (MCDA) twin pregnancies from the first trimester onward. We also report on the outcomes of MCMA twin pregnancies continuing after 28 weeks and on the neurodevelopmental outcomes of MCMA twins.

Methods: A retrospective single-center cohort study of MCMA and MCDA twin pregnancies followed from the first trimester with a fortnightly ultrasound scan. We excluded pregnancies with a major anomaly diagnosed on the first-trimester ultrasound scan. MCMA twin pregnancies were offered inpatient monitoring from 28 weeks onward, and an elective cesarean section was advised between 32 and 33 weeks. MCDA pregnancies were managed as inpatients only if medically indicated, and an elective birth between 36 and 37 weeks was recommended.

Results: We analyzed the outcomes of 52 MCMA and 671 MCDA twin pregnancies. In MCMA twins, the fetal and neonatal survival rate was 81/104 (78%) versus 1192/1342 (89%) in MCDA twins (P=0.016). Double intrauterine demise (IUD) was more common in MA than DA pairs (13% versus 3%) (P=0.002). No IUD occurred in the 40 MCMA pregnancies that continued after 28 weeks, but five women (13%) required an urgent cesarean section for fetal distress. Thirty-eight of 52 eligible infants (73%) underwent a neurodevelopmental assessment. Thirty-three (87%) had cognitive and motor development scores within normal limits. Four infants had mild cognitive or motor impairment, and one infant was diagnosed with spastic diplegia.

Conclusion: MCMA twins are associated with decreased survival rates compared to MCDA due to increased rates of double IUD. After 28 weeks, about one in eight women required an urgent delivery for fetal distress. Most infants had normal neurodevelopmental outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000526162DOI Listing
July 2022

Are there differences between monochorionic twin placentas after spontaneous and assisted conception?

Placenta 2022 Aug 13;126:171-174. Epub 2022 Jul 13.

Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium. Electronic address:

Introduction: No data are available on the placental characteristics of monochorionic twin pregnancies conceived by in vitro fertilization (IVF). This study investigates the differences between placentas from monochorionic diamniotic (MCDA) twin pregnancies conceived spontaneously and those conceived after IVF.

Methods: This is a retrospective analysis of placental data from a consecutive series of MCDA twin pregnancies followed from the first trimester. The following placental characteristics were compared between IVF versus spontaneous MCDA pregnancies: placental sharing and birth weight discordance relative to placental sharing, the placental angioarchitecture (number, type, and size of anastomoses), and the umbilical cord insertion types.

Results: Of the 256 MCDA placentas included in this analysis, 32 (12%) were conceived through IVF and 224 (88%) spontaneously. MCDA twin placentas after IVF did not differ significantly from MCDA twin placentas after spontaneous conception regarding placental sharing, birthweight discordance relative to sharing discordance, and angioarchitecture. There was a trend toward more discordant cord insertions (combination eccentric and velamentous) in IVF (25%) than in spontaneously conceived placentas (12%) (P = 0.05).

Discussion: No differences could be demonstrated between MCDA placentation after spontaneous conception and IVF. Any differences in pregnancy outcome between spontaneous and IVF conceived MCDA twins may not be related to differences in placental sharing, angioarchitecture and cord insertion type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.placenta.2022.07.004DOI Listing
August 2022

Pulmonary hypertension in congenital diaphragmatic hernia: Antenatal prediction and impact on neonatal mortality.

Prenat Diagn 2022 Jul 7. Epub 2022 Jul 7.

My FetUZ Fetal Research Center, Department of Development and Regeneration, Cluster Woman and Child, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: To determine the prevalence of pulmonary hypertension (PAH) in left-sided congenital diaphragmatic hernia (CDH); how we could predict it; and how PAH contributed to the model for mortality prediction.

Study Design: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day (d) 1, 7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio (o/e LHR), liver-herniation, fetoscopic endoluminal tracheal occlusion (FETO), and gestational age (GA) at delivery. The combined effect of pre- and postnatal variables on mortality was modeled by Cox regression.

Results: Of the 197 neonates, 56 (28.4%) died. At d1, 67.5% (133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge. At d1, o/e LHR (odds ratio (OR) 0.96) and FETO (OR 2.99) independently correlated to PAH (areas under the curve [AUC]: 0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9; AUC: 0.65). None were significant for PAH at discharge. Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction (p = 0.02), in a model including o/e LHR (HR: 0.94), FETO (HR: 0.35), liver herniation (HR: 16.78), and PAH (HR: 15.95).

Conclusions: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.6207DOI Listing
July 2022

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia.

EBioMedicine 2022 Jul 29;81:104106. Epub 2022 Jun 29.

Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. Electronic address:

Background: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH.

Methods: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied.

Findings: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure.

Interpretation: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH.

Funding: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2022.104106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244734PMC
July 2022

Timing of Delivery for Twins With Growth Discordance and Growth Restriction: An Individual Participant Data Meta-analysis.

Obstet Gynecol 2022 06 2;139(6):1155-1167. Epub 2022 May 2.

Flinders Medical Centre, Adelaide, South Australia, and the Department of Obstetrics and Gynecology, Monash University, Clayton, Victoria, Australia; the Department of Obstetrics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Julius Center for Health Sciences and Primary Care & Cochrane Netherlands, University Medical Center Utrecht, Utrecht University, Utrecht, the Department of Gynaecology and Obstetrics, GROW School of Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Department of Obstetrics and Gynecology, Haga Hospital, The Hague, the Department of Obstetrics and Gynecology, Gelre Hospitals Apeldoorn, Apeldoorn, and the Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Atrium Health, Charlotte, North Carolina; the Maternal Fetal Medicine Unit, Department of Obstetrics, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain; the Department of Obstetrics and Gynecology, Hospital das Clinicas, University of São Paulo, São Paulo, Brazil; the Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, and the Department of Obstetrics and Gynecology, Samson Assuta Ashdod University Hospital, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, the Departments of Obstetrics and Gynecology, Medicine, Community Health Sciences, and Pediatrics, and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, and the Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada; the Department of Obstetrics and Gynecology, ASST-Spedali Civili, and the Department of Clinical and Experimental Sciences, University of Brescia, Brescia, and the Fetal Therapy Unit "Umberto Nicolini" and the Department of Women, Mother and Newborn, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy; the Department of Maternal Fetal Medicine, Osaka Women's and Children's Hospital, Osaka, Japan; the Department of Fetal Medicine, The Aga Khan University, Karachi, Pakistan; the Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, Belgium; the Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon; the Departments of Clinical Biochemistry and Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; the Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland; the Mednax Center for Research, Education, Quality, and Safety, Sunrise, Florida; the Obstetrix Medical Group, Campbell, California; Unidad de Medicina Materno-Fetal, Instituto Valenciano de Infertilidad, Departamento de Pediatría, Obstetricia y Ginecología, and Servicio de Obstetricia, Hospital Universitario y Politécnico La Fe, Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain; and the Fetal Medicine Unit, St George's Hospital, the Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's University of London, and the Twins Trust Centre for Research and Clinical Excellence, London, the Institute of Applied Health Research, University of Birmingham, Birmingham, and the Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, United Kingdom.

Objective: First, to evaluate the risks of stillbirth and neonatal death by gestational age in twin pregnancies with different levels of growth discordance and in relation to small for gestational age (SGA), and on this basis to establish optimal gestational ages for delivery. Second, to compare these optimal gestational ages with previously established optimal delivery timing for twin pregnancies not complicated by fetal growth restriction, which, in a previous individual patient meta-analysis, was calculated at 37 0/7 weeks of gestation for dichorionic pregnancies and 36 0/7 weeks for monochorionic pregnancies.

Data Sources: A search of MEDLINE, EMBASE, ClinicalTrials.gov, and Ovid between 2015 and 2018 was performed of cohort studies reporting risks of stillbirth and neonatal death in twin pregnancies from 32 to 41 weeks of gestation. Studies from a previous meta-analysis using a similar search strategy (from inception to 2015) were combined. Women with monoamniotic twin pregnancies were excluded.

Methods Of Study Selection: Overall, of 57 eligible studies, 20 cohort studies that contributed original data reporting on 7,474 dichorionic and 2,281 monochorionic twin pairs.

Tabulation, Integration, And Results: We performed an individual participant data meta-analysis to calculate the risk of perinatal death (risk difference between prospective stillbirth and neonatal death) per gestational week. Analyses were stratified by chorionicity, levels of growth discordance, and presence of SGA in one or both twins. For both dichorionic and monochorionic twins, the absolute risks of stillbirth and neonatal death were higher when one or both twins were SGA and increased with greater levels of growth discordance. Regardless of level of growth discordance and birth weight, perinatal risk balanced between 36 0/7-6/7 and 37 0/7-6/7 weeks of gestation in both dichorionic and monochorionic twin pregnancies, with likely higher risk of stillbirth than neonatal death from 37 0/7-6/7 weeks onward.

Conclusion: Growth discordance or SGA is associated with higher absolute risks of stillbirth and neonatal death. However, balancing these two risks, we did not find evidence that the optimal timing of delivery is changed by the presence of growth disorders alone.

Systematic Review Registration: PROSPERO, CRD42018090866.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000004789DOI Listing
June 2022

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model.

Fetal Diagn Ther 2021 16;48(6):411-420. Epub 2021 Jun 16.

Department of Development and Regeneration, Katholieke Universiteit, Leuven, Belgium.

Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects.

Methods: Twelve fetal lambs (127-133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored.

Results: The transplacental sildenafil transfer was 2.9% (range: 1.4-7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38-78%) and increased both pulmonary blood flow (32-132%) and heart rate (13-49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion.

Conclusion: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000515435DOI Listing
November 2021

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

Ann Surg 2022 03;275(3):e586-e595

Cluster Woman and Child, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).

Background: Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO.

Methods: CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls.

Results: The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm2 vs 3.5 ± 0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ± 36 cmH2O /mL vs 113 ± 40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm2, P=0.001 and 31 ± 9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil.

Conclusion: In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000003943DOI Listing
March 2022

Prenatal diagnosis and management of congenital diaphragmatic hernia.

Best Pract Res Clin Obstet Gynaecol 2019 Jul 5;58:93-106. Epub 2019 Jan 5.

Academic Department of Development and Regeneration, Cluster Woman and Child, Biomedical Sciences, KU Leuven, Belgium; Clinical Department of Obstetrics & Gynaecology, KU Leuven, Leuven, Belgium; Institute for Women's Health, University College London, London, UK; European Reference Network on Rare and Inherited Congenital Anomalies "ERNICA". Electronic address:

Congenital diaphragmatic hernia is characterized by failed closure of the diaphragm, thereby allowing abdominal viscera to herniate into the thoracic cavity and subsequently interfering with normal lung development. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension (PHT), that is lethal in up to 32% of patients. In isolated cases, the outcome may be predicted prenatally by medical imaging and advanced genetic testing. In those fetuses with a predicted poor outcome, fetoscopic endoluminal tracheal occlusion may be offered. This procedure is currently being evaluated in a global randomized clinical trial (www.TOTALtrial.eu). We are currently investigating alternative strategies including transplacental sildenafil administration to reduce the occurrence of persistent PHT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpobgyn.2018.12.010DOI Listing
July 2019

Antenatal sildenafil administration to prevent pulmonary hypertension in congenital diaphragmatic hernia (SToP-PH): study protocol for a phase I/IIb placenta transfer and safety study.

Trials 2018 Sep 27;19(1):524. Epub 2018 Sep 27.

Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans.

Methods: This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0-32.6) and at term (sub-study 2; weeks: 36.6-40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured.

Discussion: This is the first study evaluating in-vivo transplacental passage of sildenafil in humans.

Trial Registration: EU Clinical Trials Register 2016-002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-018-2897-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161420PMC
September 2018

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia.

Prenat Diagn 2018 08 17;38(9):645-653. Epub 2018 Jul 17.

Department of Surgery, Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada.

Objective: Profiling of miR-200b expression and its targets (transforming growth factor [TGF]-β2 and ZEB2) in the surgical rabbit congenital diaphragmatic hernia (DH) model before and after tracheal occlusion (TO).

Methods: Thirty-eight timed-pregnant rabbits had left DH creation on gestational day (GD) 23. On GD28, 17 randomly selected fetuses had TO. We harvested fetuses at GD23, GD28, or GD30. We calculated lung-to-body weight ratios, processed lungs for miR-200b in situ hybridization and real-time quantitative polymerase chain reaction, and evaluated effects on downstream targets TGF-β2 or ZEB2.

Results: We obtained 16 DH fetuses (n = 7 GD28 and n = 9 GD30), 13 TO fetuses (GD30), and 38 control fetuses (n = 15 GD23, n = 11 GD28, and n = 12 GD30). Diaphragmatic hernia lungs were hypoplastic, and TO resulted in control lung-to-body weight ratio levels. Term miR-200b-3p levels were significantly upregulated in the hypoplastic compared with control ipsilateral lung (1.906 ± 0.90 vs 0.7429 ± 0.44) (P < .01). Fetal TO ipsilateral lungs displayed a variable miR-200b response on in situ hybridization and polymerase chain reaction, with levels similar to control and congenital DH lungs. The TGF-β2 was unchanged in hypoplastic and TO lungs, and ZEB2 tended to be reduced in TO compared with DH lungs (1.79 [0.4-2.9] vs 0.73 [0.5-1.4]).

Conclusions: Hypoplastic fetal rabbit lungs display upregulation of miR-200b expression although downstream targets are not different from controls. Following TO, fetal rabbit lungs display a variable miR-200b response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5318DOI Listing
August 2018

Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA).

Prenat Diagn 2018 08 23;38(9):629-637. Epub 2018 Jul 23.

Clinical Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.

Congenital diaphragmatic hernia is a rare disease associated with high mortality and morbidity. Antenatal ultrasound screening identifies more than 70% of cases, providing the opportunity for in utero referral to a tertiary care center for expert assessment and perinatal management. Additional genetic and morphologic assessment may be used to rule out associated anomalies. In isolated cases, the outcome may be predicted prenatally by medical imaging. The combination of lung size and liver herniation is a widely accepted method to stratify fetuses into groups with an increasing degree of pulmonary hypoplasia and corresponding mortality rates. Ultrasound measurement of the observed to expected lung-to-head ratio (o/e LHR) is most widely used. The o/e LHR is an independent predictor of survival and short-term morbidity. Finally, evaluation of stomach position has recently been introduced as an indirect method to estimate severity of the disease in left-sided defects, as it has been shown to correlate with the proportion of intrathoracic liver. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated CDH and individualized prediction of neonatal outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5297DOI Listing
August 2018

Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia.

Gynecol Surg 2018 8;15(1). Epub 2018 May 8.

1Academic Department of Development and Regeneration, Woman and Child, Biomedical Sciences, and Clinical Department of Obstetrics and Gynaecology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Congenital diaphragmatic hernia (CDH) is a congenital anomaly with high mortality and morbidity mainly due to pulmonary hypoplasia and hypertension. Temporary fetal tracheal occlusion to promote prenatal lung growth may improve survival. Entrapment of lung fluid stretches the airways, leading to lung growth.

Methods: Fetal endoluminal tracheal occlusion (FETO) is performed by percutaneous sono-endoscopic insertion of a balloon developed for interventional radiology. Reversal of the occlusion to induce lung maturation can be performed by fetoscopy, transabdominal puncture, tracheoscopy, or by postnatal removal if all else fails.

Results: FETO and balloon removal have been shown safe in experienced hands. This paper deals with the technical aspects of balloon insertion and removal. While FETO is invasive, it has minimal maternal risks yet can cause preterm birth potentially offsetting its beneficial effects.

Conclusion: For left-sided severe and moderate CDH, the procedure is considered investigational and is currently being evaluated in a global randomized clinical trial (https://www.totaltrial.eu/). The procedure can be clinically offered to fetuses with severe right-sided CDH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s10397-018-1041-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940711PMC
May 2018

Antenatal Medical Therapies to Improve Lung Development in Congenital Diaphragmatic Hernia.

Am J Perinatol 2018 07 16;35(9):823-836. Epub 2018 Jan 16.

The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia.

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0037-1618603DOI Listing
July 2018

Current and future antenatal management of isolated congenital diaphragmatic hernia.

Semin Fetal Neonatal Med 2017 12 21;22(6):383-390. Epub 2017 Nov 21.

Academic Department of Development and Regeneration, Clinical Specialties Research Groups, Biomedical Sciences; Clinical Department of Obstetrics and Gynaecology, KU Leuven, Leuven, Belgium; Institute for Women's Health and Institute of Child Health, University College London, London, UK. Electronic address:

Congenital diaphragmatic hernia is surgically correctable, yet the poor lung development determines mortality and morbidity. In isolated cases the outcome may be predicted prenatally by medical imaging. Cases with a poor prognosis could be treated before birth. However, prenatal modulation of lung development remains experimental. Fetoscopic endoluminal tracheal occlusion triggers lung growth and is currently being evaluated in a global clinical trial. Prenatal transplacental sildenafil administration may in due course be a therapeutic approach, reducing the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.siny.2017.11.002DOI Listing
December 2017

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

BMJ 2016 Sep 6;354:i4353. Epub 2016 Sep 6.

Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC 29403, USA.

Objective: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies.

Design: Systematic review and meta-analysis.

Data Sources: Medline, Embase, and Cochrane databases (until December 2015).

Review Methods: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation.

Results: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies.

Conclusions: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks.

Systematic Review Registration: PROSPERO CRD42014007538.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013231PMC
http://dx.doi.org/10.1136/bmj.i4353DOI Listing
September 2016

Fetal Tracheal Occlusion for Severe Pulmonary Hypoplasia in Isolated Congenital Diaphragmatic Hernia: A Systematic Review and Meta-analysis of Survival.

Ann Surg 2016 Dec;264(6):929-933

*Department of Surgery, Division of Pediatric Surgery, University of Manitoba, Winnipeg, Manitoba, Canada†Clinical department of Obstetrics and Gynaecology, UZ Leuven and Academic Department Development and Regeneration, KU Leuven, Leuven, Belgium‡Departments of Pediatrics & Child Health and Physiology & Pathophysiology, University of Manitoba, and Children's Hospital Research Institute of Manitoba, Biology of Breathing Theme, Winnipeg, Manitoba, Canada§Department Obstetrics and Gynaecology, University College London, London, United Kingdom.

Objective: To evaluate fetal survival after tracheal occlusion in fetuses with severe pulmonary hypoplasia and isolated congenital diaphragmatic hernia (CDH).

Background: Despite recent advances in neonatal intensive care, CDH still has a high mortality and morbidity. Fetoscopic endoluminal tracheal occlusion (FETO) stimulates lung growth and improves gas exchange in animal models of CDH, but the effects in humans are still under investigation.

Methods: We searched Pubmed, Cochrane, EMBASE, and Scopus databases for clinical studies on tracheal occlusion and CDH. All studies comparing FETO and a contemporary control group were included. The primary outcome was survival, with the need for oxygen on discharge the secondary outcome. Meta-analysis of outcome measures was performed and odds ratios, relative risk ratios, and 95% confidence intervals were estimated with a fixed-effects model and were reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.

Results: Between 1997 and 2015, five eligible studies describing 211 patients were included (101 control and 110 FETO). All studies selected isolated severe CDH fetuses with a lung-to-head ratio 1.0 or less and liver herniation into the thoracic cavity. FETO favored survival outcome (odds ratio 13.32; 95% confidence interval, 5.40-32.87). Meta-analysis of the secondary outcome oxygen need at discharge could not be calculated, because it was not reported in all included studies.

Conclusions: FETO improves survival in isolated CDH with severe pulmonary hypoplasia compared with the standard perinatal management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000001675DOI Listing
December 2016

Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: A systematic review.

Pediatr Pulmonol 2015 Aug 20;50(8):820-38. Epub 2015 May 20.

Department of Development and Regeneration, Cluster Organ Systems, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Objective: We aimed to systematically review all published pre-clinical research on prenatal medical treatment of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Background The neonatal mortality due to isolated CDH remains high. Whether fetal endoscopic tracheal occlusion (FETO) reduces mortality is still to be demonstrated. Therefore more potent preferentially medical therapy would be welcomed. Methods We searched MEDLINE (Pubmed), Embase and the Web of Science including all studies from the earliest date (1951) to December 2013. Article quality was assessed using the modified CAMRADES checklist. Inclusion criteria were those animal studies addressing prenatal medical interventions and principal variables were confirmation of a diaphragmatic defect, lung to body weight ratio (LBWR), formal airway morphometry or DNA/protein content. Results In total 983 articles were identified. Following abstract review, 96 articles were assessed by two authors in agreement with a third for eligibility. Of these, 43 were included in the final analysis. The median number of study quality checklist items (maximum 10) scored was 4 (IQ range: 2-5). Thirty (69.8%) of studies were in the nitrofen rat. The majority were treated with vitamins or glucocorticoids. Single studies reported some improvement in lung morphology with alternative therapies. It was impossible to identify a pattern in animal model selection or creation, mode, time point or duration of treatment and readouts. Only one study reported a sample size calculation. Conclusion Comparison in pre-clinical studies in CDH is challenging due to methodological variation. Agreed standardized methods need to be applied in future investigation of new medical therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.23206DOI Listing
August 2015

The use of human amniotic fluid stem cells as an adjunct to promote pulmonary development in a rabbit model for congenital diaphragmatic hernia.

Prenat Diagn 2015 Sep 19;35(9):833-40. Epub 2015 Jun 19.

Organ systems cluster, Department of Development and Regeneration, and Center for Surgical Technologies, Group Biomedical Sciences, KU Leuven, Leuven, Belgium.

Objective: This study aimed to evaluate the potential benefit of intra-tracheal injection of human amniotic fluid stem cells (hAFSC) on pulmonary development combined with TO in a rabbit model for CDH.

Methods: In time-mated pregnant does a left diaphragmatic defect was created at d23 (term = 31). At d28, previously operated fetuses were assigned to either TO and injection with 70 μL of phosphate buffered saline (PBS) or 1.0 × 10(6) c-Kit positive hAFSC expressing LacZ or were left untouched (CDH). Harvesting was done at d31 to obtain their lung-to-body weight ratio (LBWR), airway and vascular lung morphometry, X-gal staining and immunohistochemistry for Ki67 and surfactant protein-B (SP-B).

Results: CDH-induced pulmonary hypoplasia is countered by TO + PBS, this reverses LBWR, mean terminal bronchiole density (MTBD) and medial thickness to normal. The additional injection of hAFSC decreases MTBD and results in a non-significant decrease in muscularization of intra-acinary vessels. There were no inflammatory changes and LacZ positive hAFSC were dispersed throughout the lung parenchyma 4 days after injection.

Conclusion: HAFSC exert an additional effect on TO leading to a decrease in MTBD, a measure of alveolar number surrounding the terminal bronchioles, without signs of toxicity. © 2015 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.4621DOI Listing
September 2015

Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential.

Cytotherapy 2014 Jul 1;16(7):893-905. Epub 2014 May 1.

Dulbecco Telethon Institute at Tettamanti Research Center, Pediatric Department, University of Milano-Bicocca, Monza, Italy; Tettamanti Research Center, Pediatric Department, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy. Electronic address:

Background Aims: Cord blood (CB) and amniotic fluid (AF) could represent new and attractive mesenchymal stromal cell (MSC) sources, but their potential therapeutic applications are still limited by lack of standardized protocols for isolation and differentiation. In particular, chondrogenic differentiation has never been deeply investigated.

Methods: MSCs were obtained from CB and AF samples collected during cesarean sections at term and compared for their biological and differentiation properties, with particular interest in cartilage differentiation, in which quantitative real-time polymerase chain reaction and immunohistochemical analyses were performed to evaluate the expression of type 2 collagen, type 10 collagen, SRY-box9 and aggrecan.

Results: We were able to isolate MSCs from 12 of 30 (40%) and 5 of 20 (25%) CB and AF units, respectively. Fluorescence in situ hybridization analysis indicated the fetal origin of isolated MSC strains. Both populations expressed mesenchymal but not endothelial and hematopoietic markers, even though we observed a lower expression of human leukocyte antigen (HLA) I in CB-MSCs. No differences in proliferation rate and cell cycle analysis could be detected. After osteogenic induction, both populations showed matrix mineralization and typical marker expression. Under chondrogenic conditions, pellets derived from CB-MSCs, in contrast with AF-MSCs pellets, were significantly larger, showed cartilage-like morphology and resulted positive for chondrocyte-associated markers, such as type 2 collagen, type 10 collagen, SRY-box9 and aggrecan.

Conclusions: Our results show that CB-MSCs and AF-MSCs collected at term differ from each other in their biological and differentiation properties. In particular, only CB-MSCs showed a clear chondrogenic potential and thus could represent an ideal candidate for cartilage-tissue engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2014.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062948PMC
July 2014

Seasonal impact in the frequency of isolated spina bifida.

Prenat Diagn 2013 Oct 19;33(10):1007-9. Epub 2013 Jul 19.

Department of Obstetrics and Gynecology, University of Milano Bicocca, Monza, Italy.

Objectives: To evaluate whether a relationship exists between season at conception and occurrence of isolated spina bifida (ISB).

Study Design: All fetuses with prenatal diagnosis of ISB were analyzed according to date of conception. We compared the seasonal rates of conception between ISB fetuses and a control group consisting of a cohort of fetuses delivered during the same period from 1992 to 2009.

Results: In the control group, conceptions were equally distributed among the four seasons. Chi-square analysis showed a significantly higher rate of ISB conceptions in the fall compared with the control group (16/36, 44% vs. 12467/50533, 25%, Odds Ratio (OR) 2.44, 95% confidence interval 1.21-4.92). Not a single woman with a fetus affected by ISB took preconceptional supplement of folic acid.

Conclusions: Seasonality affects the frequency of ISB. We hypothesize that the seasonal differences may reflect dietary and climate changes with reduced intake of folic acid in the fall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.4175DOI Listing
October 2013

Perinatal complications in twin pregnancies after 34 weeks: effects of gestational age at delivery and chorionicity.

Am J Perinatol 2013 Aug 24;30(7):545-50. Epub 2012 Oct 24.

Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.

Objective: To evaluate the perinatal outcome of twins approaching term in relation to chorionicity and gestational age at delivery.

Study Design: We accessed data pertaining to a cohort of 471 twin pregnancies with certain chorionicity delivered at > 34.0 weeks' gestation. Twin gestation per se, estimated fetal weight below the 10th percentile, or any intertwin discordance was not an indication for delivery before 40.0 weeks. Predictors of adverse perinatal outcome were identified using logistic regression analysis.

Results: There were no stillbirths. Adverse neonatal outcome occurred in 27% of monochorionic versus 16% of dichorionic gestations. At multivariate analysis, lower gestational age at delivery (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.57 to 0.87), monochorionicity (OR 2.06, 95% CI 1.16-3.63), and either twin being growth-restricted (OR 2.35, 95% CI 1.22 to 4.54) were independent predictors of adverse neonatal outcome. Analysis of adverse neonatal outcome stratified by gestational age and chorionicity identified 36 to 37 weeks as optimal timing for delivery of monochorionic twins, and dichorionic twin pregnancies should be allowed to continue until term.

Conclusion: Among twin gestations delivered after 34 weeks with appropriate fetal growth, reassuring fetal status at weekly assessment, and absence of obstetric complications, delivery after 36 weeks for monochorionic twins and at term for dichorionic twins minimizes the risk of stillbirths and neonatal morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0032-1329183DOI Listing
August 2013

Placenta previa: distance to internal os and mode of delivery.

Am J Obstet Gynecol 2009 Sep 24;201(3):266.e1-5. Epub 2009 Jul 24.

Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.

Objective: The purpose of this study was to relate the mode of delivery and outcomes in a cohort of cases of placenta previa that had the last transvaginal ultrasonographic scan <28 days before delivery.

Study Design: Cases in which the placental edge overlapped the internal cervical (n = 42) underwent cesarean section delivery. Labor was allowed in those with placental edge to internal os distance of 1-10 mm (group 1, 24 women) and those with a distance of 11-20 mm (group 2, 29 women).

Results: Rates of cesarean section delivery (75% vs 31%; odds ratio, 6.7; 95% confidence interval [CI], 2-22) and of bleeding before labor (29% vs 3%; odds ratio, 11.5; 95% CI, 1.6-76.7) were higher in group 1 than in group 2. Blood loss at delivery (662 +/- 466 mL vs 510 +/- 547 mL) and rate of severe postpartum hemorrhage (21% vs 10%; odds ratio, 2.3; 95% CI, 0.5-9.7) were similar in the 2 groups.

Conclusion: More than two-thirds of women with a placental edge to cervical os distance of >10 mm deliver vaginally without increased risk of hemorrhage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2009.06.009DOI Listing
September 2009
-->