Twin anemia polycythemia sequence: Successful laser photocoagulation treatment and placental histopathological findings.

OBJECTIVE: Twin anemia polycythemia sequence (TAPS) is a rare complication of monochorionic twin pregnancies, which can occur either spontaneously or after laser photocoagulation procedure for twin to twin transfusion syndrome. TAPS is associated with poor perinatal outcomes and clear screening guidelines for this disease are lacking resulting in under-diagnosis of TAPS. CASE REPORT: The purpose of this report is to discuss a case of severe spontaneous TAPS, which was successfully treated with favorable outcome, to describe the placental histopathological findings, and to propose an algorithm for management and follow up of this rare condition. CONCLUSION: Laser photocoagulation of the placental anastomoses, despite technical challenges, can be safely performed in cases of TAPS. Even with prenatal evidence of successful resolution of TAPS, close fetal surveillance is warranted because of the persistence of placental villous immaturity.

Persistence of Villous Immaturity in Term Deliveries Following Intrauterine Transfusion for Parvovirus B19 Infection and RhD-associated Hemolytic Disease of the Fetus and Newborn.

Common causes of fetal anemia and hydrops include parvovirus B19 infection during the first 2 trimesters of pregnancy, as well as maternal alloimmunization to RhD with subsequent hemolytic disease of the fetus and newborn (HDFN) in an RhD positive fetus. Although both of these conditions have historically caused significant fetal morbidity and mortality, the advent of intrauterine transfusion (IUT) over the last few decades has dramatically improved outcomes. Prior literature has extensively documented placental changes associated with untreated parvovirus infection and RhD HDFN in intrauterine fetal demises and preterm births; however, histopathologic changes in term placentas from term infants treated with IUT have not been reported. We present placental findings in 2 cases of parvovirus B19-associated hydrops and 2 cases of RhD HDFN-associated hydrops in term infants after IUT, highlighting unique aspects that may be diagnostically useful for the examining pathologist.

Multidisciplinary team learning in the management of the morbidly adherent placenta: outcome improvements over time.

BACKGROUND: Morbidly adherent placenta (MAP) is a serious obstetric complication causing mortality and morbidity. OBJECTIVE: To evaluate whether outcomes of patients with MAP improve with increasing experience within a well-established multidisciplinary team at a single referral center. STUDY DESIGN: All singleton pregnancies with pathology-confirmed MAP (including placenta accreta, increta, or percreta) managed by a multidisciplinary team between January 2011 and August 2016 were included in this retrospective study. Turnover of team members was minimal, and cases were divided into 2 time periods so as to compare 2 similarly sized groups: T1 = January 2011 to April 2014 and T2 = May 2014 to August 2016. Outcome variables were estimated blood loss, units of red blood cell transfused, volume of crystalloid transfused, massive transfusion protocol activation, ureter and bowel injury, and neonatal birth weight. Comparisons and adjustments were made by use of the Student t test, Mann-Whitney U test, χ2 test, analysis of covariance, and multinomial logistic regression. RESULTS: A total of 118 singleton pregnancies, 59 in T1 and 59 in T2, were managed during the study period. Baseline patient characteristics were not statistically significant. Forty-eight of 59 (81.4%) patients in T1 and 42 of 59 (71.2%) patients in T2 were diagnosed with placenta increta/percreta. The median [interquartile range] estimated blood loss (T1: 2000 [1475-3000] vs T2: 1500 [1000-2700], P = .04), median red blood cell transfusion units (T1: 2.5 [0-7] vs T2: 1 [0-4], P = .02), and median crystalloid transfusion volume (T1: 4200 [3600-5000] vs T2: 3400 [3000-4000], P < .01) were significantly less in T2. Also, a massive transfusion protocol was instituted more frequently in T1: 15/59 (25.4%) vs 3/59 (5.1%); P < .01. Neonatal outcomes and surgical complications were similar between the 2 groups. CONCLUSION: Our study shows that patient outcomes are improved over time with increasing experience within a well-established multidisciplinary team performing 2-3 cases per month. This suggests that small, collective changes in team dynamics lead to continuous improvement of clinical outcomes. These findings support the development of centers of excellence for MAP staffed by stable, core multidisciplinary teams, which should perform a significant number of these procedures on an ongoing basis.

Twin anemia polycythemia sequence: a single center experience and literature review.

Twin anemia polycythemia sequence (TAPS) is defined by significant intertwin hemoglobin discordance without the amniotic fluid discordance that characterizes twin-twin-transfusion syndrome (TTTS) in monochorionic twin pregnancies. TAPS is an uncommon condition which can either occur spontaneously, or following fetoscopic laser ablation for TTTS. This complication is thought to result from chronic transfusion through very small placental anastomoses; however, the pathogenesis of TAPS remains unknown. Consequently, there is no consensus in the management of TAPS. In this article, three cases of TAPS are described and we review the literature on this uncommon pregnancy complication.

Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach.

OBJECTIVE: The purpose of this study was to test the hypothesis that a standardized multidisciplinary treatment approach in patients with morbidly adherent placenta, which includes accreta, increta, and percreta, is associated with less maternal morbidity than when such an approach is not used (nonmultidisciplinary approach). STUDY DESIGN: A retrospective cohort study was conducted with patients from 3 tertiary care hospitals from July 2000 to September 2013. Patients with histologically confirmed placenta accreta, increta, and percreta were included in this study. A formal program that used a standardized multidisciplinary management approach was introduced in 2011. Before 2011, patients were treated on a case-by-case basis by individual physicians without a specific protocol (nonmultidisciplinary group). Estimated blood loss, transfusion of packed red blood cells, intraoperative complications (eg, vascular, bladder, ureteral, and bowel injury), neonatal outcome, and maternal postoperative length of hospital stay were compared between the 2 groups. RESULTS: Of 90 patients with placenta accreta, 57 women (63%) were in the multidisciplinary group, and 33 women (37%) were in the nonmultidisciplinary group. The multidisciplinary group had more cases with percreta (P = .008) but experienced less estimated blood loss (P = .025), with a trend to fewer blood transfusions (P = .06), and were less likely to be delivered emergently (P = .001) compared with the nonmultidisciplinary group. Despite an approach of indicated preterm delivery at 34-35 weeks of gestation, neonatal outcomes were similar between the 2 groups. CONCLUSION: The institution of a standardized approach for patients with morbidly adherent placentation by a specific multidisciplinary team was associated with improved maternal outcomes, particularly in cases with more aggressive placental invasion (increta or percreta), compared with a historic nonmultidisciplinary approach. Our standardized approach was associated with fewer emergency deliveries.

Ascending in utero herpes simplex virus infection in an initially healthy-appearing premature infant.

The usual route of acquisition for intrauterine herpes simplex virus (HSV) infection is transplacental. We evaluated a premature infant with in utero acquisition of HSV resulting from ascending infection. Histopathologic evidence of chronic chorioamnionitis and positive staining with immunohistochemistry for HSV in the placenta and umbilical cord established the diagnosis. The clinical presentation was also of interest in that the infant was initially healthy appearing.

Pericardial effusion and cardiac tamponade in neonates: sudden unexpected death associated with total parenteral nutrition via central venous catheterization.

BACKGROUND: Total parenteral nutrition (TPN) via central venous catheter (CVC) is used routinely to provide adequate nutrition for neonates, especially those with very low birth weights (VLBWN). Pericardial effusion and cardiac tamponade (PCE/CT) is a potentially life-threatening CVC complication. DESIGN: This autopsy study presents the gross and histopathologic findings in 5 neonates receiving continuous TPN via CVCs, who suddenly and unexpectedly died from PCECT. RESULTS: The study population included five neonates (age 4-29 days, 3 males, 2 females, 4 VLBWN neonates, 1 full-term neonate). Chemical analysis of the milky-white PCE fluid showed high triglyceride levels (717-777 mg/dL) consistent with intralipid. Right atrial microscopic examination with the four VLBWNs showed interstitial edema and dilated lymphatics (n=4), atrial thrombus (n=1), and focal fibrinous epicardial exudate (n=1). The full-term neonate RA revealed focal myocyte coagulative necrosis, acute organizing hemorrhage, focal collagen deposition, myocardial hypertrophy, and endocardial thickening. CONCLUSIONS: Right atria in PCE/CT demonstrated marked interstitial edema and dilated fine vascular channels. Endocardial injury with permeation of hyperosmotic TPN fluid into the interstitium and egress into the pericardial sac is hypothesized as the etiology of PCE/CT. Recognition of PCE and impending CT in neonates with CVCs for TPN with expedient intervention may avoid sudden unexpected deaths.

SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice.

SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinking water. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well.

In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.

Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 µg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 µg/dL prior to treatment to 45 µg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 µg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient's ATP7A mutation (Q724H), which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

Fetal membrane patch and biomimetic adhesive coacervates as a sealant for fetoscopic defects.

Iatrogenic preterm premature rupture of membranes after fetoscopic procedures affects 10-47% of patients, secondary to the non-healing nature of membranes and the separation of layers during the entry. In this study we developed an in vitro model to mimic the uterine wall-fetal membrane interface using a water column with one end sealed with human fetal membranes and poultry breast, and a defect was created with an 11 French trocar. Further, a fetal membrane patch in conjunction with multiphase adhesive coacervates modeled after the sandcastle worm bioadhesive was tested for sealing of an iatrogenic defect. The sealant withstood an additional traction of 12 g for 30-60 min and turbulence of the water column without leakage of fluid or slippage. The adhesive is non-toxic when in direct contact with human fetal membranes in an organ culture setting. A fetal membrane patch with multiphase adhesive complex coacervates may help to seal the defect and prevent iatrogenic preterm premature rupture of the membranes.

Deoxyguanosine kinase deficiency presenting as neonatal hemochromatosis.

Mutations in DGUOK result in mitochondrial DNA (mtDNA) depletion and may present as neonatal liver failure. Neonatal hemochromatosis (NH(1)) is a liver disorder of uncertain and varied etiology characterized by hepatic and non-reticuloendothelial siderosis. To date, deoxyguanosine kinase (dGK(2)) deficiency has not been formally recognized in cases of NH. We report an African American female neonate with clinical and autopsy findings consistent with NH, and mtDNA depletion due to a homozygous mutation in DGUOK. This report highlights hepatocerebral mtDNA depletion in the differential of neonatal tyrosinemia, advocates considering dGK deficiency in cases of NH, and posits mitochondrial oxidative processes in the pathogenesis of NH.

Extraosseous Ewing sarcoma of the thyroid gland.

Ewing sarcoma of the bone is a highly malignant round-cell tumor that typically presents between 10 to 20 years of age and is more common in boys. It can have an extraosseous origin, although it is rare. We report a case of extraosseous Ewing sarcoma in the thyroid gland in a 9-year-old girl.

Cervical thymic anomalies--the Texas Children's Hospital experience.

OBJECTIVES/HYPOTHESIS: To review the presentation and management of cervical thymic cysts and ectopic thymic tissue at Texas Children's Hospital over the last 25 years. STUDY DESIGN: Case report and case series using retrospective chart review. METHODS: A case report is presented of a recently diagnosed thymic cyst highlighting diagnostic, management, and treatment strategies available for optimizing management of patients with significant mediastinal extension. We then present a retrospective review of cervical thymic anomalies at a tertiary academic medical center over a 25-year span (1983-present). Data extracted include patients' characteristics, clinical presentation, diagnostic workup, surgical management, and postoperative complications. RESULTS: Fifteen patients were found to have a pathological diagnosis of cervical thymic cyst, and 10 patients had a diagnosis of ectopic thymic tissue in the neck. This is the largest case series of cervical thymic anomalies presented in the literature to date. Patients' characteristics, diagnostic techniques, and treatment strategies are discussed. CONCLUSIONS: Cervical thymic anomalies are a rare but necessary part of the differential diagnosis of a cervical mass. Computed tomography scan can both narrow the preoperative differential diagnosis and aid in surgical planning for thymic cyst excision. A full discussion of the embryology, clinical presentation, and management of cervical thymic cysts and a review of the current literature is presented.

Antibiotic prophylaxis improves Ureaplasma-associated lung disease in suckling mice.

Ureaplasma infection is associated with increased lung disease in high-risk neonates. Our goal was to determine the impact of antibiotic prophylaxis on Ureaplasma and oxygen-induced lung disease in newborn mice. In animal model development and prophylaxis experiments, pups were randomly assigned to either 0.8 or 0.21 inspired oxygen concentration [fraction of inspired oxygen (FiO2)] from 1 to 14 d of age and either Ureaplasma or 10 B media daily from 1 to 3 d. All pups were observed for growth and survival. Surviving pups had culture and PCR evaluated for blood, bronchoalveolar lavage, and lung, and lung weights, pathology, morphometry, histology, and immunohistochemistry were determined. In prophylaxis experiments, erythromycin, azithromycin, or normal saline was given for the first 3 d, and minimum inhibitory concentration and pharmacokinetics were determined. In model development, 0.8 FiO2 and Ureaplasma infection survival and growth were significantly decreased and lung edema and inflammation were significantly increased. In prophylaxis experiments, we observed significantly improved survival and growth with azithromycin versus normal saline controls, whereas erythromycin was not significantly different from controls, and decreased inflammatory response with azithromycin versus normal saline and erythromycin. In a neonatal mouse model of Ureaplasma and oxygen-induced lung disease, appropriate antibiotic prophylaxis improves survival and morbidity and decreases lung inflammation.

Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

Pre-eclampsia affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. The clinical hallmarks of this maternal disorder include hypertension, proteinuria, endothelial dysfunction and placental defects. Advanced-stage clinical symptoms include cerebral hemorrhage, renal failure and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. An effective treatment of pre-eclampsia is unavailable owing to the poor understanding of the pathogenesis of the disease. Numerous recent studies have shown that women with pre-eclampsia possess autoantibodies, termed AT(1)-AAs, that bind and activate the angiotensin II receptor type 1a (AT(1) receptor). We show here that key features of pre-eclampsia, including hypertension, proteinuria, glomerular endotheliosis (a classical renal lesion of pre-eclampsia), placental abnormalities and small fetus size appeared in pregnant mice after injection with either total IgG or affinity-purified AT(1)-AAs from women with pre-eclampsia. These features were prevented by co-injection with losartan, an AT(1) receptor antagonist, or by an antibody neutralizing seven-amino-acid epitope peptide. Thus, our studies indicate that pre-eclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from autoantibody-induced angiotensin receptor activation. This hypothesis has obvious implications regarding pre-eclampsia screening, diagnosis and therapy.

Thoracoscopic excision of an intrathoracic mesothelial cyst in a child.

PURPOSE: The aim of this study was to highlight the unique case of an intrathoracic mesothelial cyst in a 5-year-old child that was treated with a thoracoscopic resection. BACKGROUND: Mesothelial cysts are benign cysts lined by a single layer of mesothelial cells. These rare lesions can be found on, or adjacent to, serous membranes but are only occasionally located within the thorax. In children, less than 10 intrathoracic cases have been described thus far, most of which are diaphragmatic in origin. CASE: An asymptomatic 5-year-old female presented with a left-sided mediastinal mass incidentally discovered on a chest radiograph during a work-up for scoliosis. Magnetic resonance imaging demonstrated a hypodense, nonenhancing lesion measuring 3 x 2.5 x 8 cm in the left paravertebral region. Video-assisted thoracoscopy was employed for diagnosis and excision. The thin-walled cyst was dissected free from the pleura and completely excised thoracoscopically. Histopathology showed a benign, unilocular cyst lined with a cuboidal mesothelium that stained strongly positive for cytokeratin. CONCLUSION: Mediastinal mesothelial cysts have very rarely been reported in the pediatric population. In the case presented, the benign cyst was easily excised by using a minimally invasive thoracoscopic approach. Given the appropriate indications, we feel that thoracoscopic resection is well suited for such cases.