Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.

The development of the fetal immune system during pregnancy is a well-orchestrated process with important consequences for fetal and neonatal health, but prenatal factors that affect immune activation are poorly understood. We hypothesized that chronic fetal inflammation may lead to alterations in development of the fetal immune system. To test this hypothesis, we examined neonates with gastroschisis, a congenital abdominal wall defect that leads to exposure of the fetal intestines to amniotic fluid, with resultant intestinal inflammation. We determined that patients with gastroschisis show high systemic levels of inflammatory cytokines and chemokines such as eotaxin, as well as earlier activation of CD4(+) and CD8(+) effector and memory T cells in the cord blood compared with controls. Additionally, increased numbers of T cells and eosinophils infiltrate the serosa and mucosa of the inflamed intestines. Using a mouse model of gastroschisis, we observed higher numbers of eosinophils and both type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), specifically in the portion of organs exposed to the amniotic fluid. Given the role of IL-5 produced by ILC2 in regulating eosinophil development and survival, we determined that maternal or fetal administration of the anti-IL-5 neutralizing Ab, or a depleting Ab against ILCs, can both effectively reduce intestinal eosinophilia. Thus, a congenital anomaly causing chronic inflammation can alter the composition of circulating and tissue-resident fetal immune cells. Given the high rate of prenatal and neonatal complications in these patients, such changes have clinical significance and might become targets for fetal therapy.

Non-Immune Hydrops Fetalis: Do Placentomegaly and Polyhydramnios Matter?

OBJECTIVES: Polyhydramnios and placentomegaly are commonly observed in nonimmune hydrops fetalis (NIHF); however, whether their ultrasonographic identification is relevant for prognosis is controversial. We evaluated outcomes of fetal or neonatal death and preterm birth (PTB) in cases of NIHF alone and in those with polyhydramnios and/or placentomegaly (P/PM). METHODS: We conducted a retrospective cohort of singletons with NIHF evaluated between 1994 and 2013. Nonimmune hydrops fetalis was defined as 2 or more abnormal fluid collections, including ascites, pericardial effusion, pleural effusion, and skin edema. Primary outcomes were intrauterine fetal demise (IUFD) and neonatal death. Secondary outcomes were PTB (<37, < 34, and <28 weeks) and spontaneous PTB. Outcomes were compared between cases of NIHF alone and NIHF with P/PM. RESULTS: A total of 153 cases were included; 21% (32 of 153) had NIHF alone, and 79% (121 of 153) had NIHF with P/PM. There was no significant difference in neonatal death (38.1% versus 43.0%; P = .809) between the groups. Intrauterine fetal demise was seen more frequently in NIHF alone (34.4% versus 17.4%; P = .049). Nonimmune hydrops fetalis-with-P/PM cases were more likely to deliver before 37 weeks (80.0% versus 57.1%; P = .045) and before 34 weeks (60.0% versus 28.6%; P = .015) and to have spontaneous PTB (64.4% versus 33.3%; P = .042). Adjusted odds ratios accounting for the etiology of NIHF supported these findings, with the exception of IUFD. CONCLUSIONS: Compared to NIHF alone, pregnancies with NIHF and P/PM had a lower risk of IUFD and were at increased risk of PTB (<37 and <34 weeks) and spontaneous PTB. This information may help providers in counseling patients with NIHF and supports the need for close antenatal surveillance.

Maternal-fetal cellular trafficking: clinical implications and consequences.

PURPOSE OF REVIEW: Maternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between mother and fetus during pregnancy. This results in the presence of fetal cells in the maternal circulation, known as fetal microchimerism, and maternal cells in the fetal circulation, known as maternal microchimerism. The biologic role of this transplacental cellular trafficking during pregnancy is not known, although it has been implicated in development of the fetal immune system, tolerance mechanisms during pregnancy, tissue repair in autoimmune disease and cancer, and immune surveillance. RECENT FINDINGS: Clinical utility of MFCT has been identified in prenatal testing for aneuploidies and prediction of pregnancy complications. Additionally, this transplacental passage of cells has been implicated in the delicate balance between immunologic priming and tolerance, which can influence the occurrence of autoimmune disease and transplantation outcomes. Ongoing studies are evaluating the utility of microchimerism in predicting the risk of graft rejection in transplantation. SUMMARY: In this review, we will discuss the clinical implications of MFCT in pregnancy, fetal surgery, autoimmune disease, transplantation, and cancer.

Prenatal diagnosis of spontaneous septostomy in dichorionic diamniotic twins and review of the literature.

OBJECTIVE: We present 2 cases of spontaneous septostomy in dichorionic diamniotic twins and review the literature regarding the incidence, etiology, and complications of this condition. METHODS: The following key words were used in the literature search: "rupture dividing membrane twin," "disruption dividing membrane twin," "pseudomonoamniotic twin," "spontaneous septostomy twin," "interfetal membrane disruption," "intertwin membrane rupture," and "intertwin membrane disruption." RESULTS: We present 2 cases in which an intertwin membrane defect was found prenatally in dichorionic diamniotic twins. In both cases, a portion of one twin's body was found traversing the spontaneous septostomy and in the sac of its cotwin. Umbilical cord Doppler studies showed no abnormalities in either case as the cord crossed the membrane disruption. In both cases, the fetuses had no notable sequelae from the ruptured intertwin membrane. The literature review revealed no cases of spontaneous septostomy in dichorionic diamniotic twins but 15 cases in monochorionic diamniotic twins. Possible etiologies include chorioamnionitis, trauma or physical rupture by the fetuses, developmental disturbances represented by amniotic plica, and polyhydramnios. In cases of monozygotic twins, a vascular etiology could explain this rare defect with formation of anastomoses of the outer embryonic vasculature. Complications of the spontaneous septostomy cases identified in the literature included cord entanglement (8 cases), preterm delivery (9 cases), and death (8 cases), although our 2 cases had minimal complications. CONCLUSIONS: Spontaneous septostomy in dichorionic diamniotic twins has not previously been reported.

Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α.

Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor-α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.

Clinical management of infantile cholelithiasis.

PURPOSE: Infantile cholelithiasis is a rare disease process, and management strategies are poorly defined. We therefore examined the risk factors, complications, and management of this disease at our institution. METHODS: We retrospectively reviewed infants with cholelithiasis diagnosed on ultrasound between 1997 and 2013. Details of the patient's medical history, presentation, imaging findings, laboratory values, and treatment were reviewed and analyzed. RESULTS: Over the 16-year period, 50 infants were evaluated for cholelithiasis. Thirty-seven (74%) had at least one risk factor for gallstone development which included total parenteral nutrition, diuretic therapy, cephalosporin antibiotic treatment, sepsis, congenital heart disease (CHD), prematurity, or a malabsorptive gastrointestinal condition. Thirteen (26%) infants were symptomatic, most commonly presenting with emesis and jaundice. Complications from gallstones included choledocholithiasis (9), cholecystitis (3), and pancreatitis (1). Nearly half (6/13) of patients with complicated cholelithiasis had CHD. Of infants presenting with complications, 9 had a cholecystectomy, most commonly via a laparoscopic approach, 2 had an ERCP for choledocholithiasis, and 2 were medically managed. In patients managed conservatively, resolution of gallstones occurred in 25%. CONCLUSIONS: Infantile cholelithiasis has variable outcomes ranging from spontaneous resolution to choledocholithiasis or cholecystitis. While patients with complicated cholelithiasis often undergo an operation, infants <1year of age have higher anesthetic and surgical risks. Conservative management with ERCP or medical treatment can also be successful, which offers an alternative to operative intervention in properly selected patients.

Spontaneous biliary perforation in infancy: Management strategies and outcomes.

PURPOSE: Infantile spontaneous biliary perforation is rare with variable management strategies ranging from nonoperative treatment to complex operations such as biliary-enteric reconstruction. Biliary fistula and portal vein thrombosis are known complications, though outcomes are poorly defined. METHODS: We assessed the incidence of spontaneous biliary perforation in infants <1 year old using a population database. Next, we describe 4 patients treated at our institution and review all reported cases within the past 25 years. RESULTS: The incidence of spontaneous biliary perforation is 1.5 in 1,000,000 live births. Over the past 25 years, 90 cases were reported, over half of which were initially managed with a surgical drainage procedure. The most common reason for failure of this strategy was CBD obstruction. Our 4 patients were successfully managed without biliary reconstruction despite 2 presenting with CBD obstruction. Reported complications occurred in 22% of patients, most frequently biliary fistula requiring delayed biliary reconstruction. CONCLUSIONS: Surgical drainage is an effective method for treatment of infantile spontaneous biliary perforation; however a persistent biliary fistula should prompt evaluation for distal CBD obstruction. Though biliary-enteric anastomosis is the historic procedure of choice for persistent fistula, with improvements in endoscopic and percutaneous treatment, extensive biliary reconstruction may be avoided in the future.

The many faces of hydrops.

PURPOSE: Fetal hydrops arises from multiple disease processes and can portend a grim prognosis. We reviewed our experience with hydropic fetuses to understand relevant antenatal anatomic and physiologic predictors of survival. METHODS: We reviewed fetal ultrasounds and echocardiograms of hydropic fetuses evaluated from 1996 to 2013. RESULTS: Overall neonatal survival in 167 fetuses was 44% (range, 0-75%) and was influenced by the underlying disease process. The anatomic distribution of fluid varied and was not significantly different between survivors and nonsurvivors. Univariate analysis indicated that resolution of hydrops and delivery at a later gestational age were predictive of survival (OR: 5.7 (95% CI: 2.5-13.2) and OR: 1.3 (95% CI: 1.1-1.4), respectively). Fetal intervention also improved survival in some diseases. Echocardiograms were reviewed to group fetuses with similar cardiac physiology and defined categories with high or low/normal cardiothoracic ratio (CTR). Among patients with a high CTR, the cardiovascular profile score was predictive of survival (p=0.009). CONCLUSION: Survival in hydrops depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery and not on the specific anatomic manifestations of hydrops. In hydropic fetuses with high CTRs, the cardiovascular profile score may be a useful prognostic indicator.

Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia.

This review focuses on the emerging field of non-surgical in-utero therapies in the management of fetal pulmonary hypoplasia and pulmonary hypertension associated with congenital diaphragmatic hernia (CDH). These experimental approaches include pharmacologic as well as stem-cell-based strategies. Current barriers of non-surgical therapies toward clinical translation are emphasized. As the severity of CDH will likely influence the efficacy of any in-utero therapy, the current status of prenatal imaging and the role of novel biomarkers, especially those related to fetal inflammation, are also reviewed.

In utero hematopoietic cell transplantation for hemoglobinopathies.

In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor-specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.

Neonatal ovarian torsion complicated by intestinal obstruction and perforation, and review of the literature.

We present a case of neonatal ovarian torsion complicated by bowel obstruction and perforation and review the literature regarding the incidence of bowel obstruction in neonatal ovarian cysts, the presentation, and treatment. A term neonate was prenatally diagnosed with a cystic abdominal mass palpable on physical examination. A postnatal abdominal x-ray showed paucity of gas in the left hemiabdomen with rightward displacement of bowel loops. Exploratory laparotomy on day 2 of life revealed a large cystic mass in the left lower quadrant consistent with a torsed left ovary, an omental band causing strangulation of the bowel mesentery, and a perforation of the distal ileum. Our literature search revealed 19 reported cases of neonatal ovarian cysts resulting in bowel obstruction. Infants may present with a palpable abdominal mass, respiratory distress, as well as signs and symptoms of intestinal obstruction. Two mechanisms exist for bowel obstruction: adhesions caused by a torsed necrotic ovary and mass effect of a large ovarian cyst, often measuring 9 to 10 cm in diameter. Options to treat ovarian cysts include antenatal or postnatal aspiration, laparoscopy, and laparotomy. Cysts less than 4 to 5 cm can be observed, whereas operative intervention is indicated in symptomatic cases and in persistent or enlarging ovarian cysts.

An isolated echogenic heart focus is not an indication for amniocentesis in 12,672 unselected patients.

OBJECTIVE: To evaluate the risk of Down syndrome in fetuses with a heart echogenic focus using the Bayes theorem and likelihood ratios in an unselected population. METHODS: We prospectively evaluated 12,672 second-trimester sonographic features and extracted and examined a population with an echogenic focus for chromosomal anomalies. RESULTS: There were 479 cases of echogenic focus; 90.4% were isolated, whereas 9.6% had associated findings. Eleven patients had fetuses with trisomy 21 (9 per 10,000). Eight of those did not have an echogenic focus, whereas 3 had a heart echogenic focus. Only 1 fetus with trisomy 21 had an isolated echogenic focus. The positive likelihood ratio for total cases of a heart echogenic focus and trisomy 21 was 7.25, whereas for an isolated echogenic focus, the positive likelihood ratio was 2.66. CONCLUSIONS: The results of the statistical analysis showed that the risk of aneuploidy is increased in fetuses with an echogenic intracardiac focus; however, the finding should prompt a detailed structural survey and correlation with a priori risk. Amniocentesis need not be offered to patients who are otherwise at low risk and have an isolated echogenic intracardiac focus.