Russell W. Jennings

Correction of congenital diaphragmatic hernia in utero: VI. hard-earned lessons

Extensive experimental work suggests that repair of congenital diaphragmatic hernia (CDH) in utero may salvage severely affected fetuses who otherwise have a high expected mortality despite optimal postnatal care including extracorporeal membrane oxygenation (ECMO). We have reported that repair of CDH in utero is physiologically sound and safe for the mother, but technically difficult especially when the liver is herniated into the fetal chest. In the 3 years since our last report (1989 to 1991), 61 additional patients were referred for consideration of in utero repair. Fetal repair was attempted in 14 with severe isolated left CDH diagnosed before 24 weeks gestation. Five fetuses died intraoperatively, from technical problems related to reduction of incarcerated liver and uterine contractions--problems which have subsequently been surmounted. Nine patients were successfully repaired. Four babies survived, two delivered prematurely and died, and three died in utero within 48 hours of repair. Intraoperative technical problems have been overcome; the factors limiting successful outcome are postoperative physiologic management of the maternal-fetal unit and effective tocolysis to control preterm labor.

Balloon Dilation of Severe Aortic Stenosis in the Fetus Potential for Prevention of Hypoplastic Left Heart Syndrome: Candidate Selection, Technique, and Results of Successful Intervention

Background—Preventing the progression of fetal aortic stenosis (AS) to hypoplastic left heart syndrome (HLHS) requires identification of fetuses with salvageable left hearts who would progress to HLHS if left untreated, a successful in utero valvotomy, and demonstration that a successful valvotomy promotes left heart growth in utero. Fetuses meeting the first criterion are undefined, and previous reports of fetal AS dilation have not evaluated the impact of intervention on in utero growth of left heart structures. Methods and Results—We offered fetal AS dilation to 24 mothers whose fetuses had AS. At least 3 echocardiographers assigned a high probability that all 24 fetuses would progress to HLHS if left untreated. Twenty (21 to 29 weeks’ gestation) underwent attempted AS dilation, with technical success in 14. Ideal fetal positioning for cannula puncture site and course of the needle (with or without laparotomy) proved to be necessary for procedural success. Serial fetal echocardiograms after intervention demonstrated growth arrest of the left heart structures in unsuccessful cases and in those who declined the procedure, while ongoing left heart growth was seen in successful cases. Resumed left heart growth led to a 2-ventricle circulation at birth in 3 babies. Conclusions—Fetal echocardiography can identify midgestation fetuses with AS who are at high risk for developing HLHS. Timely and successful aortic valve dilation requires ideal fetal and cannula positioning, prevents left heart growth arrest, and may result in normal ventricular anatomy and function at birth.

Reversal of Parenteral Nutrition–Associated Liver Disease in Two Infants With Short Bowel Syndrome Using Parenteral Fish Oil: Implications for Future Management

Here we report the reversal of cholestasis in 2 infants with intestinal failure and parenteral nutrition–associated liver disease. Treatment involved the substitution of a conventional intravenous fat emulsion with one containing primarily omega-3 fatty acids. Biochemical tests of liver function improved significantly. One child was removed from the liver transplantation list because of improved hepatic function, and the second child had complete resolution of cholestasis while solely on parenteral nutrition. This suggests that fat emulsions made from fish oils may be an effective means of treating and preventing this often-fatal condition. A randomized, controlled trial is necessary to study the efficacy of this new approach to parenteral nutrition–associated liver disease.

Fetal liver position and perinatal outcome for congenital diaphragmatic hernia

Despite advances in postnatal care, patients born with a congenital diaphragmatic hernia (CDH) suffer substantial morbidity and mortality. The present study was undertaken to determine the prognostic influence of prenatally‐diagnosed liver herniation in the hemithorax in fetuses with CDH.

Creation of an Atrial Septal Defect In Utero for Fetuses With Hypoplastic Left Heart Syndrome and Intact or Highly Restrictive Atrial Septum

Background—Infants born with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum face a neonatal mortality of at least 48% despite early postnatal left atrial decompression and palliative surgery. Prenatal left atrial decompression has been suggested as a means of improving these outcomes. This study reports the feasibility of fetal catheterization to create an interatrial communication and describes technical considerations. Methods and Results—Seven fetuses at 26 to 34 weeks’ gestation with hypoplastic left heart syndrome and intact or highly restrictive atrial septum underwent attempted prenatal intervention. Under ultrasound guidance, the atrial septum was approached with a needle introduced percutaneously from the maternal abdominal surface. In 6 of 7 fetuses, the atrial septum was successfully perforated, with balloon dilation of this iatrogenic defect resulting in a small but persistent interatrial communication. There were no maternal complications. One fetus died after the procedure. The remaining fetuses were liveborn at term, although 4 died as neonates. Conclusions—Ultrasound-guided fetal atrial septoplasty consisting of septal puncture and balloon dilation is feasible and can be performed percutaneously to minimize maternal risk. Although we have not demonstrated any positive clinical impact to date, it is our hope that further technical evolution will ultimately enable prenatal left atrial decompression and improvement of outcomes in fetuses with hypoplastic left heart syndrome and intact atrial septum.

Fetal tissue engineering from amniotic fluid

BACKGROUND We have recently shown, in an animal model, that amniotic fluid can be a source of cells for fetal tissue engineering. This study was aimed at determining whether fetal tissue constructs could also be engineered from cells normally found in human amniotic fluid. STUDY DESIGN Cells obtained from the amniotic fluid of pregnant women at 15 to 19 weeks of gestation (n=6) were cultured in Dulbeccos Modified Eagles medium (Sigma Chemical, St Louis, MO) containing 20% fetal bovine serum and 5 ng/mL basic fibroblast growth factor in a 95% humidified, 5% CO(2) chamber at 37 degrees C. A subpopulation of morphologically distinct cells was then mechanically isolated from the rest and selectively expanded. The lineage of this subpopulation of amniocytes was determined by immunofluorescent staining with antibodies against standard intermediate filaments and surface antigens. Cell proliferation rates were determined by oxidation assay. After cell expansion, colonies of amniocytes were statically and dynamically seeded onto both unwoven, 1-mm-thick polyglycolic acid polymer scaffold and acellular human dermis for 72 hours. The resulting constructs were analyzed by scanning electron microscopy. RESULTS Amniocytes stained positively for smooth muscle actin, vimentin, cytokeratin 18, and fibroblast surface protein, and negatively for desmin, cluster of differentiation 31, and von Willebrands factor (Dako, Carpenteria, CA). These findings are consistent with a mesenchymal, fibroblast-myofibroblast cell lineage. Mesenchymal amniocytes could be rapidly expanded in culture, based on results of the proliferation assay. Scanning electron microscopy of amniocyte constructs revealed dense, confluent layers of cells surrounding the polymer matrices and firm cell adhesion to both PGA and Alloderm (Lifecell Corp, Branchburg, NJ) scaffolds. No evidence of cell death was observed. CONCLUSIONS Subpopulations of fetal mesenchymal cells can be consistently isolated from human amniotic fluid and rapidly expanded in vitro. Human mesenchymal amniocytes attach firmly to both polyglycolic acid polymer and acellular human dermis. The amniotic fluid can be a valuable and practical cell source for fetal tissue engineering.

Bronchial Atresia Is Common to Extralobar Sequestration, Intralobar Sequestration, Congenital Cystic Adenomatoid Malformation, and Lobar Emphysema

Congenital cystic adenomatoid malformation (CCAM), intralobar sequestration (ILS), extralobar sequestration (ELS), and lobar emphysema (LE) are well-accepted entities; however, certain findings are common to all, particularly the parenchymal maldevelopment characterizing CCAM. Isolated reports have described bronchial atresia (BA) in some specimens in all 4 entities, but this finding has not been evaluated in a prospective manner. With the aid of a dissecting microscope, we prospectively examined 47 lung specimens resected during the past 4 years and submitted with the clinical impression of ELS (n = 11), ILS (n = 11), CCAM (n = 20), LE (n = 4), and airway-esophageal communication (n = 1). Most lesions were detected by prenatal ultrasound and were resected during infancy. The clinical impression and pathologic findings were compared. Pathologic examination revealed atresia of a lobar, segmental, or subsegmental bronchus in 100% of ELS, 82% of ILS, 70% of CCAM, and 50% of LE (those clinically recognized to have BA or minor CCAM) cases. Parenchymal maldevelopment that characterizes CCAM was present in 100% of CCAM cases (as expected by definition) as well as in 91% of ELS, 91% of ILS, and 50% of LE (those with BA) cases. Bronchial atresia is present in all ELS, most ILS and CCAM, and some LE cases, and its detection is greatly enhanced with the dissecting microscope. Bronchial atresia and CCAM nearly always coexist. It may be that both have the same etiopathogenesis with anatomic differences accounted for by aberrant genetic programs or other insults, perhaps modified by time of onset or duration.

Perineal one-stage pull-through for Hirschsprung's disease

PURPOSE The aim of this study was to present the strategy of a one-stage repair of Hirschsprungs Disease (HD) performed via a transanal approach. METHODS Ten consecutive neonates and one toddler underwent transanal repair for biopsy-proven HD. A rectosigmoid transition zone was suggested by contrast enema in all patients. The mean age at operation for the neonates was 4 days. A mucosal dissection was begun 0.5 cm proximal to the dentate line. Once the correct plane was established, up to 15 cm of bowel can be resected without ligating vessels or performing a transabdominal dissection. The proximal extent of dissection was delineated by the presence of ganglion cells seen on frozen section analysis. RESULTS The mean operating time was 105 minutes. There were no intraoperative or postoperative complications. All children had the presence of ganglion cells confirmed postoperatively on permanent sections. The mean hospital stay was 2 days. All children averaged three to six bowel movements per day without oral or enema therapy. CONCLUSIONS The perineal one-stage operative pull-through (POOP) procedure for Hirschsprungs disease is a quick and easy adaptation of a well-described technique of transanal mucosectomy. Long-term follow-up will be required to determine whether bowel function is better that that seen after traditional staged repairs.

Fetal Neuroblastoma: Prenatal Diagnosis and Natural History

Obstetrical sonography has helped diagnose and define the features of some congenital malformations and tumors. We present five fetal neuroblastomas detected by routine prenatal sonography. All were adrenal tumors diagnosed between 26 and 39 weeks gestation. All 5 tumors were completely resected postnatally and the patients have remained disease free from 2 months to 10 years after resection without adjuvant therapy. A literature review collated 16 other cases of fetal neuroblastoma detected by sonography between 29 and 38 weeks gestation. These cases included 1 cervical, 1 thoracic, and 14 adrenal tumors. Thirteen neonates had Evans stage I or II tumors, and three had more advanced disease. Eleven mothers did not have hypertension or preeclampsia during the pregnancy, and the neonates all had stage I or II disease. Four mothers had hypertension or preeclampsia. Three of these neonates had stage IV or IVS disease with liver metastases, and all three had fetal hydrops. Review of the congenital neuroblastoma literature documented 71 cases diagnosed soon after birth, and several of these cases had unusual features that could have been detected by prenatal ultrasound. Four of the tumors were so large that dystocia resulted and fetal dismemberment was required for delivery. Eight of the tumors metastasized to the placenta, and 1 metastasized to the umbilical cord with subsequent fetal death. We conclude that fetal neuroblastoma can be diagnosed by prenatal sonography. Accurate staging is difficult by sonography, but in mothers with no preeclampsia symptoms the chance of widely disseminated disease is small.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal diaphragmatic wounds heal with scar formation

Fetal wound healing is fundamentally different from wound healing in the adult. Although experimental work in mice, rats, rabbits, monkeys, and sheep has demonstrated that fetal healing occurs without inflammation and scarring, all of these studies have been limited to fetal skin wounds. Whether all fetal tissues heal in a regenerative-like fashion is unknown. Amniotic fluid exposure may play an important role in scarless fetal skin wound healing, but the effect of amniotic fluid on fetal mesothelial wound healing has not been characterized. To investigate these questions we created bilateral linear diaphragmatic wounds in 100-day gestation fetal lambs (term = 145 days). The right thoracotomy was closed to exclude amniotic fluid. In contrast, the left thoracotomy was fashioned into an Eloesser flap which permitted the left diaphragmatic wound to be continually bathed in amniotic fluid. Wounds were harvested after 1, 2, 7, or 14 days and analyzed by light microscopy and immunohistochemistry with antibodies to collagen types I, III, IV, and VI. Whether bathed in or excluded from amniotic fluid, the mesothelial-lined diaphragm healed with scar formation and without evidence of muscle regeneration. Interestingly, diaphragmatic wounds exposed to amniotic fluid were covered by a thick fibrous collagen peel similar to that seen in gastroschisis bowel. These findings indicate that not all fetal tissues share the unique scarless healing properties of fetal skin.