S. Christopher Derderian

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.

Outcomes of fetal intervention for primary hydrothorax

OBJECTIVE Primary hydrothorax is a rare congenital anomaly with outcomes ranging from spontaneous resolution to fetal demise. We reviewed our experience with fetuses diagnosed with primary hydrothorax to evaluate prenatal management strategies. METHODS We reviewed the records of patients evaluated for fetal pleural effusions at our Fetal Treatment Center between 1996 and 2013. To define fetuses with primary hydrothorax, we excluded those with structural or genetic anomalies, diffuse lymphangiectasia, immune hydrops, and monochorionic diamniotic twin gestations. RESULTS We identified 31 fetuses with primary hydrothorax, of whom 24 had hydrops. Hydropic fetuses were more likely to present with bilateral effusions. Of all fetuses with primary hydrothorax, 21 had fetal interventions. Survival without hydrops was 7/7 (100%), whereas survival with hydrops depended on whether or not the patient had fetal intervention: 12/19 (63%) with intervention and 1/5 (20%) without intervention. Premature delivery was common (44%) among those who had fetal intervention. CONCLUSIONS Fetal intervention for primary hydrothorax may lead to resolution of hydrops, but preterm birth and neonatal demise still occur. Understanding the pathophysiology of hydrops may provide insights into further prenatal management strategies, including targeted therapies to prevent preterm labor.

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.

Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

PURPOSE Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. METHODS CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. RESULTS Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002). CONCLUSIONS PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.

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 patients 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.

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.

Fetoscopic approach to amniotic band syndrome

BACKGROUND Amniotic band syndrome (ABS) is an uncommon complication of pregnancy that can result in fetal demise. METHODS We present our experience with fetoscopic amniotic band release. RESULTS Five patients underwent fetoscopic amniotic band release for preoperatively diagnosed ABS involving at least one extremity. Four of five patients were found to have involvement of the umbilical cord at the time of fetoscopy. One of these four did not have the band released and underwent fetal demise at 24 weeks. All four survivors had good functional outcomes of affected limbs. Two patients developed membrane separation and had preterm deliveries at 32 weeks gestation whereas the other two carried to term. No maternal complications were noted. CONCLUSIONS Fetoscopic amniotic band release is safe. Umbilical cord involvement is difficult to assess preoperatively, but when it is present should be treated to reduce the risk of fetal demise.

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.

Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells

IUHCT of human cord blood-derived CD34+ cells into fetal NSG mice results in systemic multilineage engraftment with human cells.Preconditioning with in utero injection of an anti-c-Kit receptor antibody (ACK2) results in an improved rate of engraftment.

Feto-Maternal Cell Trafficking and Labor

Maternal-fetal cellular trafficking is a complex process in which fetal cells migrate into the maternal circulation and maternal cells migrate into the fetal circulation. This phenomenon can result in long-lived microchimerism within the mother and her progeny. Recently, examination of the levels of trafficking between the mother and fetus has gained momentum with improvements in strategies to detect microchimerism. The long-term consequences of trafficking have been explored in the context of transplant tolerance and autoimmunity. In addition to long-term effects, trafficking may also lead to pregnancy complications, such as preeclampsia, intrauterine growth restriction, and preterm labor, which are the leading causes of morbidity and mortality during pregnancy. Fetal surgery, a strategy that has improved survival in many fetuses with severe congenital anomalies, may enhance cellular trafficking and is often accompanied by pregnancy complications. However, the connection between the two entities remains unknown. In this chapter, we will review current techniques to detect fetal and maternal microchimerism and implications of microchimerism as it relates to maternal and fetal/child health, with a particular emphasis on pregnancy complications. Finally, we will explore the effects congenital abnormalities and fetal surgery on maternal-fetal cellular trafficking.