[show abstract][hide abstract] ABSTRACT: Objective
To analyze perinatal outcome in monoamniotic (MA) pregnancies that underwent antenatal surgical interventions for fetal complications. Methods
Review of all MA pregnancies treated with antenatal surgical interventions in 3 Fetal Treatment Centers between 2000 and 2013. Indications were twin-twin transfusion syndrome, twin reversed arterial perfusion sequence, discordant anomalies or elective reduction. We analyzed associations between indication, type of intervention, perinatal survival and gestational age (GA) at birth, and compared our results with a systematic review of the literature. ResultsFifty-eight MA pregnancies were included. Median GA at treatment was 18.0 weeks (range: 13.1 - 33.0). Procedures included cord coagulation plus transection (n = 42), cord coagulation without transection (n = 7), laser coagulation of placental anastomoses (n = 7), and one case each with interstitial laser and radiofrequency ablation. Median GA at birth was 34 weeks (range 16.0 - 41.0) and 75% (53/71) of fetuses intended to survive indeed survived. Literature review: 20 articles, reporting on a total of 45 cases of surgically treated MA pregnancies, showing similar outcome results. Conclusion
We present the largest series concerning surgical interventions in complicated MA pregnancies. Despite being rare in experienced hands, a 75% survival is achieved. Collaboration between centers, data-sharing and benchmarking may further improve outcome. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Gene therapy of the lung has the potential to treat life-threatening diseases such as cystic fibrosis (CF) and α-1-antitrypsin or surfactant deficiencies. A major hurdle for successful gene therapy is the development of an immune response against the transgene and/or viral vector. We hypothesized that by targeting the airways in the perinatal period, induction of an immune response against the vector particle could be prevented due to immaturity of the immune system, in turn allowing repeated gene transfer later in adult life to ensure long-term gene expression. Therefore, we readministered recombinant adeno-associated viral vector serotype 5 (rAAV2/5) to mouse airways at 3 and 6 months after initial perinatal gene transfer. Our findings demonstrate that perinatal rAAV2/5-mediated gene transfer to the airways avoids a strong immune response. This immunological ignorance allows the readministration of an autologous vector later in adult life, resulting in efficient and stable gene transfer up to 7 months, without evidence for a decrease in transgene expression. Together, these data provide a basis to further explore perinatal gene therapy for pulmonary conditions with adequate gene expression up to 7 months.
[show abstract][hide abstract] ABSTRACT: Large solid sacrococcygeal teratomas (SCT) can cause high output cardiac failure and fetal or neonatal death. We describe the outcomes of minimally invasive antenatal procedures for the treatment of fetal SCT. Material and methodsCase review of 5 fetuses with large SCT's treated antenatally using minimally invasive techniques and systematic literature review on fetal therapy for solid SCT's.
Five women were referred between 17.7-26.6 weeks gestation for large fetal SCT's with evidence of fetal cardiac failure. Vascular flow to the tumors was interrupted by fetoscopic laser ablation (n = 1), radiofrequency ablation (RFA, n = 2) and interstitial laser ablation +/- vascular coiling(n = 2). There were 2 intra-uterine fetal deaths. The other 3 cases resulted in preterm labor within 10 days of surgery. One neonate died. Two survived without procedure related complications but had long-term morbidity related to prematurity. Systematic literature review revealed 15 SCT's treated minimally invasively for (early) hydrops. Including ours, 6 of 20 hydropic fetuses survived after minimally invasive therapy (30%). Survival after RFA or interstitial laser was 45% (n = 5/11). Of 12 fetuses treated for SCT without obvious hydrops, 67% (n = 8/12) survived. Mean gestational age at delivery after minimally invasive therapy was 29.7 ± 4.0 weeks. Survival after open fetal surgery in hydropic fetuses was 55% (n = 6/11) with a mean gestational age at delivery of 29.8 ± 2.9 weeks.
Fetal therapy can potentially improve perinatal outcomes for hydropic fetuses with solid SCT's but is often complicated by intrauterine death and preterm birth.
Ultrasound in Obstetrics and Gynecology 01/2014; · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The vagina and surrounding structures have been shown to remodel during pregnancy. Our objective was to characterize the biomechanical properties of the vagina in the rodent model in vivo utilizing three-dimensional (3D) ultrasound.
The vagina was visualized by ultrasound after distention by increasing pressures throughout pregnancy (15 and 18 days) and after vaginal delivery (7 and 30 days postpartum) of six longitudinally followed rodents. The pelvic floor compliance and vaginal cross-sectional area of the proximal, middle, and distal vagina were compared with those of nulliparous control animals (n = 8).
The compliance of the pelvic floor increased 3.5- and 5.4-fold at days 15 and 18 of pregnancy respectively (p < 0.05). The compliance of the pelvic floor decreased 7 days postpartum, and it continued to decrease after vaginal delivery through the 30 day time point. Using 3D ultrasound, we could characterize the remodeling of the vagina throughout pregnancy and after vaginal delivery. We could reconstruct the vaginal wall cross-sectional area and found the distal vaginal wall throughout pregnancy to be distended more than the proximal and middle regions.
The observed changes in vaginal area may improve our understanding of which areas are at risk of injury during delivery. Further, 3D ultrasound allowed the determination of the in vivo biomechanical properties of the vagina. This image modality is beneficial for characterizing the in vivo properties of the vagina and surrounding pelvic support longitudinally within an animal.
International Urogynecology Journal 01/2014; · 2.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
Large congenital diaphragmatic hernia may require prosthetic correction. Acellular collagen matrix were introduced to avoid complications due to the use of synthetic patches. We tested 3 different ACM for reconstruction of an abdominal wall defect in an animal model that mimics the fast growth during infancy.
Pelvisoft® and 2 investigational ACM were used for primary reconstruction of a full thickness abdominal wall defect. 3 months-old rats (n = 26) were allowed to survive for 90 days after implantation. Anatomical, tensiometric and histological analysis were performed. Based on good outcomes, we did the same with 1 month-old rats (n = 54). Unoperated rats were used for obtaining reference tensiometric values of selected native tissues.
Major wound complications were exclusively observed in 1 month-old rats. All explants in both groups thinned significantly (p < 0.03) and had an elastic modulus increasing over time, far above that from native tissues at 90 days of life. Both investigational ACM induced a more vigorous foreign body reaction than Pelvisoft®.
The shift from 3 to 1 month-old rats was associated with wound complications. Pelvisoft® showed a better biocompatibility than the 2 investigational ACM. Passive biomechanical properties of all explants were still not comparable to that of native tissues.
[show abstract][hide abstract] ABSTRACT: The objective of this study was to document early neonatal (7 days) pulmonary outcome in the rabbit model for preterm birth and hyperoxia induced lung injury. Preterm pups were delivered at 28 days (term=31days; early saccular phase of lung development) by cesarean section, housed in an incubator and gavage fed for 7 days. Pups were divided into the following groups: (1) normoxia (21% O2; normoxia-group), (2) and hyperoxia (>95% O2; hyperoxia-group). Controls were pups born at term who were housed in normoxic conditions (control-group). Outcome measures were survival, pulmonary function tests using the whole body plethysmograph and forced oscillation technique and lung morphometry. There was a significant difference in survival of preterm pups whether they were exposed to normoxia (83.3%) or hyperoxia (55.9%). Hyperoxic exposure was associated with increased tissue damping and elasticity and decreased static compliance compared to normoxic controls (p<0.01). Morphometry revealed an increased linear intercept and increased mean wall transection length, which translates to larger alveoli with septal thickening in hyperoxia compared to normoxia (p<0.01). In conclusion, the current experimental hyperoxic conditions to which preterm pups are exposed induce the typical clinical features of bronchopulmonary dysplasia. This model will be used to study novel preventive or therapeutic interventions.
[show abstract][hide abstract] ABSTRACT: Poor growth is a common problem in twin pregnancies, and management poses some unique challenges as the wellbeing of both twins have to be taken into account at all times. The decision to deliver the twins to prevent an intrauterine demise of the growth-restricted twin will, therefore, depends on the chances of intact postnatal survival of both twins. In monochorionic twins, management is complicated further by the fact that the wellbeing of one twin critically depends on that of the other twin because of the shared circulation. In the event of demise of the growth-restricted twin, the larger twin may also die or sustain brain damage because of an acute exsanguination into the feto-placental unit of its demised co-twin. In the pre-viable period, invasive fetal therapy may, therefore, be indicated to protect the appropriately growing twin.
Best practice & research. Clinical obstetrics & gynaecology 12/2013; · 1.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: To describe the development of an anatomically accurate simulator in order to aid the training of a perinatal team in the insertion and removal of a fetal endoscopic tracheal occlusion (FETO) balloon in the management of prenatally diagnosed congenital diaphragmatic hernia (CDH).
An experienced perinatal team collaborated with a medical sulptor to design a fetal model for the FETO procedure. Measurements derived from a 28-week fetal MRI were used in the the development of an anatomically precise simulated airway within a silicone rubber preterm fetal model. Clinician feedback was then used to guide multiple iterations of the model with serial improvements in the anatomic accuracy of the simulator airway.
An appropriately sized preterm fetal mannequin with a high-fidelity airway was developed. The team used this model to develop surgical skills with balloon insertion, and removal, and to prepare the team for an integrated response to unanticipated delivery with the FETO balloon still in-situ.
This fetal mannequin aided in the ability of a fetal therapy unit to offer the FETO procedure at their centre for the first time. This model may be of benefit to other perinatal centres planning to offer this procedure. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Postmortem MRI (pmMRI) is increasingly used in perinatology, typically as an alternative or complement to conventional necropsy for central nervous system anomalies. Overall it provides reliable information on structural malformations, but was shown to be of limited use in examining fetal heart.
We aimed to assess the fetal heart on 3-Tesla pmMRI in a consecutive series of fetuses with structural congenital heart defects (CHD) and to determine diagnostic evaluation limits in case of CHD.
A single center database was retrospectively reviewed. Only fetuses having CHD of functional significance were included. Fetal cardiac anatomy was assessed on T2-weighted 3D multiplanar reconstructed images acquired using isovolumetric voxel size (0.3-0.8mm(3) ) that allows to visualize cardiac structures in situ in multiple fetal body planes. Cardiac pathology was classified into complex and isolated CHD. Based on clinically relevant findings pmMRI was considered either diagnostic or not diagnostic.
A total of 24 fetuses were included in this study. The median gestational age (GA) was 22weeks and 2days (range 12w5d-34w6d). The median delay between delivery of the fetus and MR was 6hours30minutes (range 1h30min-19h). PmMRI was diagnostic for 12 out of 13 (92.3%) complex-CHD and for six out of eleven (54.5%) isolated-CHD. In case of valvular malformation a tentative diagnosis was reached in 7/11 cases (64%) based on indirect features.
Postmortem MRI is a valid diagnostic tool for CHD in fetuses beyond 16 weeks up to term. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Purpose:To evaluate the clinical utility of chromosomal microarrays for prenatal diagnosis by a prospective study of fetuses with abnormalities detected on ultrasound.Methods:Patients referred for prenatal diagnosis due to ultrasound anomalies underwent analysis by array comparative genomic hybridization as the first-tier diagnostic test.Results:A total of 383 prenatal samples underwent analysis by array comparative genomic hybridization. Array analysis revealed causal imbalances in a total of 9.6% of patients (n = 37). Submicroscopic copy-number variations were detected in 2.6% of patients (n = 10/37), and arrays added valuable information over conventional karyotyping in 3.9% of patients (n = 15/37). We highlight a novel advantage of arrays; a 500-kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Variants of uncertain significance were revealed in 1.6% of patients (n = 6/383).Conclusion:We demonstrate the added value of chromosomal microarrays for prenatal diagnosis in the presence of ultrasound anomalies. We advocate reporting back only copy-number variations with known pathogenic significance. Although this approach might be considered opposite to the ideal of full reproductive autonomy of the parents, we argue why providing all information to parents may result in a false sense of autonomy.Genet Med advance online publication 31 October 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.168.
Genetics in medicine: official journal of the American College of Medical Genetics 10/2013; · 3.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Measuring the stiffness of the cervix might be useful in the prediction of preterm delivery or successful induction of labour. For that purpose a variety of methods for quantitative determination of physical properties of the pregnant cervix have been developed. Herein we review studies on the clinical application of these new techniques. They are based on the quantification of mechanical, optical, or electrical properties associated with increased hydration and loss of organization in collagen structure. Quasi-static elastography determines relative values of stiffness hence it can identify differences in deformability. Quasi-static elastography unfortunately cannot quantify in absolute terms the stiffness of the cervix. Also, the current clinical studies did not demonstrate the ability to predict the time point of delivery. In contrast, measurement of maximum deformability of the cervix (e.g. quantified with the cervical consistency index, CCI) provided meaningful results, showing an increase in compliance with gestational age. These findings are consistent with aspiration measurements on the pregnant ectocervix indicating a progressive decrease of stiffness along gestation. CCI and aspiration measurements therefore represent promising techniques for quantitative assessment of the biomechanical properties of the cervix. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: A mathematical model to estimate membrane tensions (Mt) at the urogenital hiatus and midpelvis in patients with and without prolapse is proposed. For that purpose the complex structures of the pelvic floor were simplified and, based on assumptions concerning geometry and loading conditions, Laplace's law was used to calculate Mt. The pelvic cavity is represented by an ellipsoid in which the midpelvic and hiatal sections are described by an ellipse. The downwards forces within the pelvis (Fin) are in equilibrium with the support forces within its walls (Fw). Fin is the abdominal pressure (PABD) multiplied by the area A of the ellipse. The force inside the tissues (Fw) is distributed along the circumference of the ellipse C. The Mt can be approximated as Mt = (PABD.A)/C (N/m). Mt-α accounts for the angle α which describes tissue orientation with respect to the anatomical section and is calculated as Mt-α = Mt/sin(α).
We conducted a retrospective study on archived magnetic resonance imaging scans (n = 20) and ultrasound images in patients with (n = 50) or without prolapse (n = 50) and measured actual geometrical variables. PABD was measured in patients with and without prolapse (n = 20).
Mt at the urogenital hiatus at rest is 0.35 N/cm. They significantly increase with the Valsalva manoeuvre, by a factor of 2.3 (without prolapse) to 3.6 (with prolapse).
Calculated Mt are much lower than what is reported for the abdominal cavity. Prolapse patients have significantly larger Mt, which during the Valsalva manoeuvre increase more than in healthy subjects.
International Urogynecology Journal 10/2013; · 2.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: With this pictorial essay we aimed to provide gestational age specific reference ranges of relevant fetal structures using micro- ultrasound, as well as its correlation with postmortem MRI and whole body sections.
Time-mated pregnant rabbits (n = 24) were assessed once at various gestational ages in the second half of pregnancy (15, 17, 21-23, 25-28 and 30-31 days; term = 31 days). We obtained biometric data, together with Doppler flow patterns in the ductus venosus (DV), umbilical artery (UA) and umbilical vein. After euthanasia, micro-ultrasound images were compared with images obtained by 9.4 Tesla MRI and whole body paraffin sections at 15,23,26 and 28 days.
We constructed biometric normative curves, which showed a significant correlation with gestational age. The pulsatility index (PI) in the UA decreased with gestation (PI = 5.746 - 0.2969(GA) + 0.004931(GA)(2) ; R(2) = 0.30), whereas pulsatility index for veins (PIV) in the DV remained constant (median PIV = 0.82 (0.60-1.12)). In this report we provide an anatomical atlas of fetal thoracic development using both micro-ultrasound and MRI.
We describe anatomical fetal leporine development as can be visualized by micro-ultrasound and MR imaging. The reported reference ranges may be useful for researchers using the fetal rabbit model. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Congenital Diaphragmatic Hernia (CDH) is a foetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in foetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and more recently chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify CNVs associated with isolated CDH.
We perform a prospective genome wide screen for copy number variations using chromosomal microarrays on 75 foetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH.
The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis we provide strong evidence for several novel dosage sensitive candidate genes associated with CDH.
Chromosomal microarray analysis detects submicroscopic copy number variations associated with isolated CDH or CDH with cardiovascular malformations. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Left-sided congenital diaphragmatic hernia (LCDH) is often associated with a smaller left ventricle, yet in most cases this finding has no apparent functional impact and seems to resolve after birth. In right-sided CDH (RCDH) little is known about fetal cardiac size and function. The aim of this study was to evaluate fetal cardiac anatomy and function in RCDH and to compare values with normal controls.
Fetal echocardiography was performed in 17 consecutive cases with isolated RCDH and 17 gestational age matched controls. Two-dimensional measurements included ventricular and outflow tract diameters. Doppler ultrasound was used to measure the flow pattern in the ductus venosus, over the pulmonary and aortic valve, right and left ventricular myocardial performance index and the E/A wave ratio over the atrioventricular valves. Stroke volumes, cardiac output and shortening fractions were calculated.
Median GA at evaluation was 27.4 weeks (IQR 24.4-28.9 weeks). RCDH cases were associated with a significantly smaller right ventricle and pulmonary valve diameter. Furthermore, stroke volume and cardiac output from the right ventricle were also lower than in controls. Myocardial contractility however appeared normal.
Despite significantly reduced right ventricular dimensions and cardiac output, cardiac contractility was normal in a cohort of fetuses with right-sided CDH.
Ultrasound in Obstetrics and Gynecology 07/2013; · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the independent and combined value of gestational age, fetal weight, feto-placental Doppler, and myocardial performance index for the prediction of individual risk of early (≤7 days) intrauterine fetal death (IUFD) after laser therapy in twin-twin transfusion syndrome (TTTS).
A consecutive series of 215 cases of TTTS treated with laser therapy in 3 centers was prospectively studied. Ultrasound evaluation within 24 hours of surgery included estimated fetal weight discordance (EFWD), umbilical artery (UA) pulsatility index (PI) and diastolic flow evaluation, middle cerebral artery PI (MCAPI) and peak systolic velocity (MCAPSV), ductus venosus PI and atrial flow assessment and modified myocardial performance index. Logistic regression analysis was used to explore the association of preoperative parameters with IUFD.
IUFD occurred in 17 (7.9%) of recipients and 33 (15.3%) donors (p = 0.016). The only independent predictors of IUFD in recipients was MCAPSV > 1.5MoM (OR = 22, p = 0.015), but this event was present in only 3% of recipients. In donors, reverse end diastolic flow in the UA (OR = 14.748, p = 0.033), EFWD (OR = 1.054, p = 0.036) and gestational age (OR = 0.757, p = 0.046) were independent predictors.
In TTTS, preoperative fetal assessment can identify independent risk factors for early postoperative IUFD, particularly in donors. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: We aimed to measure whether website provided information about congenital diaphragmatic hernia (CDH) and fetal therapy for severe cases provides added value compared to clinical counseling of parents.
This is a single center study in 102 couples who earlier opted for FETO because of isolated severe CDH. They were asked to fill out an anonymized web based survey of 12 questions. Then they were offered access to information on the webpages of the randomized Tracheal Occlusion to Accelerate Lung growth (TOTAL) trial. One week later their appreciation was measured again by a second questionnaire.
82 (80 %) parents completed the first questionnaire and 48 (47 %) the entire survey. Several items became more clear to the parents after reading the website, such as the length of hospital stay (23.2% prior to webinformation, 60.4% after; P = 0.004), maternal risk, or the requirement of fetal anesthesia for FETO (43.9 % resp. 79.2 %; P = <0.001).
Complementing prenatal counseling on CDH and FETO by standardized information via website is perceived by parents as of added value. Maternal risks and the need for fetal medication need more clarification during the verbal counseling prior to prenatal interventions. This article is protected by copyright. All rights reserved.