Steffi Mayer

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. Copyright

The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and meta‐analysis of observational studies

We conducted a meta‐analysis to assess the correlation of lung volume and liver position measured by magnetic resonance imaging (MRI) with survival until discharge in fetuses with isolated congenital diaphragmatic hernia (CDH).

Maternal administration of betamethasone inhibits proliferation induced by fetal tracheal occlusion in the nitrofen rat model for congenital diaphragmatic hernia: a placebo-controlled study

PurposeFetal tracheal occlusion (TO) is offered to fetuses with severe pulmonary hypoplasia due to congenital diaphragmatic hernia (CDH). TO induces lung growth, but even when performed minimally invasive, there is a risk for iatrogenic preterm delivery. Whenever this is anticipated, maternal glucocorticoids (GC) may be given to enhance lung maturation. The pulmonary effects of GC in fetuses with CDH that underwent TO are yet poorly defined. Therefore, we conducted a placebo-controlled study in the nitrofen (NF) rat model for CDH.MethodsPregnant rats were gavage fed NF or olive oil (OO) on ED9.5. At ED19.0, fetuses were either assigned to TO or left untouched. Maternal betamethasone (BM) or saline (PLAC) was administered on ED20. Necropsy was done on ED21.5 to obtain lung-to-body-weight ratio (LBWR), and perform quantitative RT-PCR and fluorescent immunostaining for Ki-67 and proliferating cell nuclear antigen (PCNA) in fetal lungs.ResultsCDH fetuses had a lower LBWR than normal fetuses, but comparable pulmonary PCNA and Ki-67 expression levels. TO increased LBWR, irrespective of maternal BM or PLAC. However, BM but not PLAC inhibited proliferation in TO and unoperated fetuses.ConclusionRats with NF-induced CDH have hypoplastic lungs with normal proliferation indices. TO triggers proliferation, an effect countered by BM.

Single-incision multiport laparoscopy does not cause more pain than conventional laparoscopy: a prospective evaluation in children undergoing appendectomy.

BACKGROUND The benefit of single-incision multiport laparoscopy (SIMPL) remains a matter of vivid discussion. For good reason it has been speculated that SIMPL causes more postoperative pain, because a minilaparotomy is required to place the multiport system. We prospectively evaluated postoperative pain scores and requirement of analgesic medication following conventional laparoscopic (CL) versus SIMPL appendectomy in children. METHODS The access for laparoscopic appendectomy was decided upon the surgeons preference. Between April and October 2010, individual abdominal pain scores at 8, 16, 24, 48, and 72 hours postoperatively as well as the incidence of umbilical or shoulder pain and the total amount of peri- and postoperative analgesics, operative time, length of hospital stay, and demographics were assessed. Analgesics (paracetamol and/or metamizole, 15 mg/kg body weight) were administered regularly or on inquiry of the patient. Data are presented as means±standard deviation tested at a significance level of P<.05. RESULTS All operations were laparoscopically completed without conversion or addition of extra ports. Thirty-nine patients (8 SIMPL appendectomy) at a mean age of 12.3±2.4 years and a mean body mass index of 19.16±3.2 kg/m(2) were included. Equal operation times were observed (SIMPL: 68.5±19.9 minutes versus CL: 66.2±19.5 minutes). There were no significant differences for the individual pain scores or the incidence of umbilical and shoulder pain between study groups. The total amount of required analgesic medication was significantly lower after SIMPL appendectomy (SIMPL: 65.73±43.8 mg/kg versus CL: 106.39±46.4 mg/kg, P=.04). CONCLUSION In summary, the present study substantiates the evidence that SIMPL appendectomy in children and adolescents is not only feasible but also beneficial for the patient without translation into increased postoperative pain. Presently, we are conducting a randomized, blinded study to validate these findings.

Congenital myelomeningocele – do we have to change our management?

BackgroundEagerly awaiting the results of the Management of Myelomeningocele Study (MOMS) and with an increasing interest in setting up intrauterine myelomeningocele repair (IUMR), the optimal management of patients suffering from congenital myelomeningocele (MMC) has become a matter of debate again. We performed a cross-sectional study at our referral-center for MMC to determine the outcome for our expectantly managed patients.Materials and methodsA computed chart review at our institution revealed 70 patients suffering from MMC. Forty-three patients were eligible for the study and analyzed further. A retrospective analysis was performed only in patients that underwent MMC repair within the first two days of life and were seen at our outpatient clinic between 2008 and 2009 for a regular multidisciplinary follow-up. Data were collected on: gestational age (GA) and weight at birth, age at shunt placement and shunt status after the first year of life, radiological evidence for Arnold-Chiari malformation (ACM) and tethered cord (TC), need for surgery for TC, bladder function, lower leg function and educational level. Data were compared to published results for IUMR and to studies of historical controls.ResultsPatients were born with MMC between 1979 and 2009 and are now 13.3 ± 8.9 (mean ± SD) years of age. At birth, mean GA was 37.8 ± 2.3 weeks and mean weight was 2921.3 ± 760.3 g, both significantly higher than in IUMR patients. Shunt placement in our cohort was required in 69.8% at a mean age of 16.0 ± 10.7 days, which was less frequent than for historical controls. Amongst our cohort, radiological observations showed 57.1% had ACM II and 41.9% had TC. Only two of our patients underwent a surgical correction for TC. Clean intermittent catheterization was performed in 69.7% of our patients, 56.4% were (assisted) walkers and 64.1% attended regular classes, both comparable to historical controls.ConclusionsWith a close and interdisciplinary management by pediatric surgeons, neurologists and urologists, the long-term outcome of patients suffering from MMC can currently be considered satisfactory. With respect to the known drawbacks of fetal interventions for mother and child, especially preterm delivery, the results of the MOMS trial should be awaited with caution before proceeding with a complex intervention like IUMR.Eagerly awaiting the results of the Management of Myelomeningocele Study (MOMS) and with an increasing interest in setting up intrauterine myelomeningocele repair (IUMR), the optimal management of patients suffering from congenital myelomeningocele (MMC) has become a matter of debate again. We performed a cross-sectional study at our referral-center for MMC to determine the outcome for our expectantly managed patients. A computed chart review at our institution revealed 70 patients suffering from MMC. Forty-three patients were eligible for the study and analyzed further. A retrospective analysis was performed only in patients that underwent MMC repair within the first two days of life and were seen at our outpatient clinic between 2008 and 2009 for a regular multidisciplinary follow-up. Data were collected on: gestational age (GA) and weight at birth, age at shunt placement and shunt status after the first year of life, radiological evidence for Arnold-Chiari malformation (ACM) and tethered cord (TC), need for surgery for TC, bladder function, lower leg function and educational level. Data were compared to published results for IUMR and to studies of historical controls. Patients were born with MMC between 1979 and 2009 and are now 13.3 ± 8.9 (mean ± SD) years of age. At birth, mean GA was 37.8 ± 2.3 weeks and mean weight was 2921.3 ± 760.3 g, both significantly higher than in IUMR patients. Shunt placement in our cohort was required in 69.8% at a mean age of 16.0 ± 10.7 days, which was less frequent than for historical controls. Amongst our cohort, radiological observations showed 57.1% had ACM II and 41.9% had TC. Only two of our patients underwent a surgical correction for TC. Clean intermittent catheterization was performed in 69.7% of our patients, 56.4% were (assisted) walkers and 64.1% attended regular classes, both comparable to historical controls. With a close and interdisciplinary management by pediatric surgeons, neurologists and urologists, the long-term outcome of patients suffering from MMC can currently be considered satisfactory. With respect to the known drawbacks of fetal interventions for mother and child, especially preterm delivery, the results of the MOMS trial should be awaited with caution before proceeding with a complex intervention like IUMR.

Diaphragm Repair with a Novel Cross-Linked Collagen Biomaterial in a Growing Rabbit Model.

Background Neonates with congenital diaphragmatic hernia and large defects often require patch closure. Acellular collagen matrices (ACM) have been suggested as an alternative to synthetic durable patches as they are remodeled by the host or could also be used for tissue engineering purposes. Materials and Methods 2.0x1.0 cm diaphragmatic defects were created in 6-weeks old New-Zealand white rabbits. We compared reconstruction with a purpose-designed cross-linked ACM (Matricel) to 4-layer non-cross-linked small intestinal submucosa (SIS) and a 1-layer synthetic Dual Mesh (Gore-Tex). Unoperated animals or animals undergoing primary closure (4/0 polyglecaprone) served as age-matched controls. 60 (n = 25) resp. 90 (n = 17) days later, animals underwent chest x-ray and obduction for gross examination of explants, scoring of adhesion and inflammatory response. Also, uniaxial tensiometry was done, comparing explants to contralateral native diaphragmatic tissue. Results Overall weight nearly doubled from 1,554±242 g at surgery to 2,837±265 g at obduction (+84%). X-rays did show rare elevation of the left diaphragm (SIS = 1, Gore-Tex = 1, unoperated control = 1), but no herniation of abdominal organs. 56% of SIS and 10% of Matricel patches degraded with visceral bulging in four (SIS = 3, Matricel = 1). Adhesion scores were limited: 0.5 (Matricel) to 1 (SIS, Gore-Tex) to the left lung (p = 0.008) and 2.5 (Gore-Tex), 3 (SIS) and 4 (Matricel) to the liver (p<0.0001). Tensiometry revealed a reduced bursting strength but normal compliance for SIS. Compliance was reduced in Matricel and Gore-Tex (p<0.01). Inflammatory response was characterized by a more polymorphonuclear cell (SIS) resp. macrophage (Matricel) type of infiltrate (p<0.05). Fibrosis was similar for all groups, except there was less mature collagen deposited to Gore-Tex implants (p<0.05). Conclusions Matricel induced a macrophage-dominated inflammatory response, more adhesions, had appropriate strength but a lesser compliance compared to native tissue. The herein investigated ACM is not a viable option for CDH repair.

Albumin as an adjunct to tracheal occlusion in fetal rats with congenital diaphragmatic hernia: a placebo-controlled study

OBJECTIVE We sought to investigate effects of intratracheal albumin injection prior to tracheal occlusion (TO) on lung proliferation in fetal rats with nitrofen-induced congenital diaphragmatic hernia. STUDY DESIGN On embryonic day 19, nitrofen-exposed fetuses underwent TO, TO and 50 microL of either intratracheal albumin 20% or saline, or remained untouched. Main outcome at embryonic day 21.5 was expression of the proliferation marker Ki-67. Secondary outcomes were lung-to-bodyweight ratio (LBWR), tropoelastin expression, density and spatial distribution of elastin, pulmonary/alveolar morphometry, and fetal survival. RESULTS TO increased Ki-67 messenger RNA and LBWR. Albumin further increased LBWR and density of Ki-67-positive cells but also fetal mortality. TO with or without adjuncts induced elastin deposits at the tips of arising secondary crests, increased air space size, and decreased septal thickness. CONCLUSION TO had effects on lung proliferation and advanced the morphologic appearance. Addition of albumin increased density of proliferating cells and LBWR, yet at the expense of additional fetal loss.

A longer tracheal occlusion period results in increased lung growth in the nitrofen rat model

Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with severe congenital diaphragmatic hernia. Limited data are available regarding the effect of duration of TO on lung development. Our objective was to evaluate the effects of long (2 and 2.5 days) versus short (1 day) TO on lung development in rats with nitrofen‐induced diaphragmatic hernia.

A Novel Surgical Approach for Intratracheal Administration of Bioactive Agents in a Fetal Mouse Model

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome(1,2) or hyperoxic injuries of the neonatal lung(3). Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)(4), genetic variants of surfactant deficiencies(5) and α1-antitrypsin deficiency(6). Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individuals immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies(7). In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep(8), and even in a clinical setting(9), but has to date not been performed before in a mouse model. When studying the potential of fetal gene therapy for genetic diseases such as CF, the mouse model is very useful as a first proof-of-concept because of the wide availability of different transgenic mouse strains, the well documented embryogenesis and fetal development, less stringent ethical regulations, short gestation and the large litter size. Different access routes have been described to target the fetal rodent lung, including intra-amniotic injection(10-12), (ultrasound-guided) intrapulmonary injection(13,14) and intravenous administration into the yolk sac vessels(15,16) or umbilical vein(17). Our novel surgical procedure enables researchers to inject the agent of choice directly into the fetal mouse trachea which allows for a more efficient delivery to the airways than existing techniques(18).

Laparoscopic Resection of a Colonic Venous Malformation in an Infant

Introduction: Venous malformations in the bowel are extremely rare in children. A few case reports recommend the laparoscopic assisted mobilization of the lesion and conversion to an external resection and anastomosis. However, in infants with large tumors of the descending and sigmoid colon, this strategy would require a laparotomy. Case Description/Technique Description: A 2-year-old girl presented with painless rectal bleeding and anemia. Ultrasonography and magnetic resonance imaging (MRI) revealed a 5 3 3-cm angiodysplastic lesion of the distal bowel. Colonoscopy verified a vascular malformation of the sigmoid with exophytic growth. Performing a 4-port laparoscopy (3–5 mm), we identified the lesion along with grossly distended blood vessels in the sigmoid colon. After hitching it to the anterior abdominal wall, we carefully mobilized the lesion. To avoid a laparotomy of equivalent size or significant bleeding during externalization, the mass was resected laparoscopically using the LigaSure device (Covidien, Mansfield, Massachusetts). Finally an all-in laparoscopic anastomosis was fashioned (4–0 Vicryl, interrupted stitches; Ethicon, Somerville, New Jersey). The inspection of both remaining colonic margins showed no macroscopic evidence of the disease. The specimen was placed in a bag and morcellated with forceps through one slightly extended port site until it could be extracted. Operative time was 269 minutes. Histology described a venous malformation. The postoperative course was uneventful, and after a follow-up of more than 1.5 years, the girl remains free of symptoms. Conclusion: An all-in laparoscopic resection of a vascular malformation of the colon can be performed successfully and with excellent cosmetic results in children and even infants.