Cell free fetal DNA to triage antenatal rhesus immune globulin: Is it really cost-effective in the United States?

OBJECTIVE: To compare the efficacy and costs of three different strategies of antenatal rhesus immune globulin (RhIG) administration in a US population. METHODS: A decision tree analysis was undertaken for universal antenatal RhIG administration based on RhD serologic paternity testing, universal administration without paternity, and selective antenatal RhIG administration using cell free fetal DNA (cfDNA) for RHD fetal typing. Rates of alloimmunization were calculated. Charges were determined for laboratory testing and obstetrical and neonatal treatments for the first pregnancy and cases of alloimmunization in the following pregnancy. RESULTS: The largest number of new RhD alloimmunization cases resulted from a strategy of universal RhIG that included paternity. Fewer cases resulted from a selective strategy; the least number of cases were associated with a universal approach that discounted paternity. When the costs of first pregnancies and alloimmunized second pregnancies were combined, a universal strategy that excludes paternity had the least costs followed by a selective strategy followed by a universal strategy that included paternity. CONCLUSION: The use of cfDNA to determine the selective use of antenatal RhIG would not be cost-effective in the United States. Universal antenatal RhIG without paternity is more effective in preventing new cases of alloimmunization than the current ACOG guideline.

Middle cerebral artery peak systolic velocity in perinatal cytomegalovirus infection.

A middle cerebral artery peak systolic velocity value (MCA-PSV) persistently greater than 1.5 times the median of the normal population is utilized to detect moderate and severe anemia in fetuses at risk. Cytomegalovirus (CMV) is the most common perinatal infection and can cause fetal anemia. We present four cases with CMV perinatal infection. Although their MCA-PSV values were the highest recorded in normal as well as in anemic fetuses, only two of them developed moderate or severe anemia. These findings suggest that high MCA-PSV values in cases with perinatal CMV infection may have a different pathophysiologic mechanism than anemia.

Fetal anemia.

The diagnosis and management of fetal anemia has been at the forefront of advances in the fields of fetal physiology, immunology, fetal imaging, and fetal therapy among others. Alloimmunization and parvovirus infection are the leading cause of fetal anemia in the United States. The middle cerebral artery peak systolic velocity (MCA-PSV) diagnoses fetal anemia. Its discovery is considered one of the most important achievements in fetal medicine. Accumulation of experience in recent years as well as refinement of surgical techniques have led to safer invasive procedures. It is expected that long term follow-up of affected pregnancies, continues to reflect all these improvements in care. It is also expected that treatment of other less common causes of fetal anemia becomes more frequently reported and that the management principles of fetal anemia are successfully applied to other fetal pathologies.

Exploring the Pharmacokinetic Profile of Remifentanil in Mid-Trimester Gestations Undergoing Fetal Intervention Procedures.

Background: Indications for surgery during pregnancy have increased. Specifically fetal interventions have increased from conditions that were considered lethal like twin-twin transfusion syndrome and severe fetal anemia to non-lethal conditions like myelomeningocele. The optimal anesthetic agent for in utero surgery is yet to be determined. Success of the procedure is often dictated by the efficacy of the anesthetic to immobilize the fetus without over-sedating mom. Remifentanil is used as preferred agent due to its short half-life however pharmacokinetics in pregnancy is unknown. Objective: To determine the pharmacokinetic parameters of remifentanil in a mid-trimester pregnant patient population undergoing fetal intervention. Study Design: A validated liquid chromatography assay with ultraviolet absorbance was employed to estimate maternal serum remifentanil levels. Blood samples were obtained at baseline and at selected time points: 5, 15, 30, 45, 60 min after the beginning of the remifentanil infusion and at 15, 30, and 60 min post end of infusion. Results: Ten pregnant patients were enrolled in the study however only eight patients had sampling obtained at all time points. The mean gestational age was 22.2 (±2.7) weeks, maternal age was 27.8 (±5.1) years and body mass index was 29.6 (±6.3). After receiving a continuous infusion of remifentanil, mean total dose was 975.3 µg, Cmin was 2.0 ng/mL and Cmax was 8.4 ng/mL. A two-compartment model best described the plasma remifentanil data. Mean pharmacokinetic parameters were: volume of distribution (Vdc) = 124.6 L (16.2-530.8 L), maternal remifentanil total clearance (Clt) = 170.7 L/h (17.7-486.9 L/h), and half-life (t½) = 0.6 h (0.2-0.9 h). The maternal remifentanil area under the curve (AUC) ranged from 2.7 to 21.7 µg/L*h. The mean alpha-acidic glycoprotein was 124.8 mg/dL (81.3-149.8). Conclusion: The pharmacokinetic profile of remifentanil in pregnant women is similar to previously reported general population profiles. This data did provide potential rationale for the clinical observations why when remifentanil is dosed based on non-pregnant guidelines, it did not uniformly provide adequate fetal immobilization as per anecdotal perception of operating fetal surgeons. These findings are important for the development of further clinical studies to optimize dosing for surgery during pregnancy including the estimation of placental transfer and total fetal exposure.

Serial intrauterine transfusions for a hydropic fetus with severe anemia and thrombocytopenia caused by parvovirus: lessons learned.

Introduction Fetal exsanguination is a rare complication of cordocentesis. Successful correction of fetal thrombocytopenia is essential for the reduction of risks. Case Report A 25-year-old, gravida 3, P2-0-0-0-2, was referred at 27 weeks of gestation for evaluation of newly diagnosed nonimmune hydrops secondary to parvovirus infection. Despite the use of ancillary platelet transfusions to correct the severe fetal thrombocytopenia, prolonged bleeding from the cord puncture site still occurred, necessitating five intrauterine transfusions to ultimately correct the fetal anemia. Conclusions The use of a smaller-diameter procedure needle, correction of the fetal thrombocytopenia early in the procedure, and external cord compression with the ultrasound transducer were ultimately successful measures in allowing for minimal loss of transfused red cells from the intravascular compartment.

Management and prevention of red cell alloimmunization in pregnancy: a systematic review.

OBJECTIVE: To evaluate the application of new technologies to the management of the red cell alloimmunized pregnancy. DATA SOURCES: We searched three computerized databases for studies that described treatment or prevention of alloimmunization in pregnancy (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials [1990 to July 2012]). The text words and MeSH included Rhesus alloimmunization, Rhesus isoimmunization, Rhesus prophylaxis, Rhesus disease, red cell alloimmunization, red cell isoimmunization, and intrauterine transfusion. METHODS OF STUDY SELECTION: Of the 2,264 studies initially identified, 246 were chosen after limiting the review to those articles published in English and crossreferencing to eliminate duplication. TABULATION, INTEGRATION, AND RESULTS: Both authors independently reviewed the articles to eliminate publications involving less than six patients. Special emphasis was given to publications that have appeared since 2008. CONCLUSION: Quantitative polymerase chain reaction can be used instead of serology to more accurately determine the paternal RHD zygosity. In the case of unknown or a heterozygous paternal RHD genotype, new DNA techniques now make it possible to diagnose the fetal blood type through cell-free fetal DNA in maternal plasma. Serial Doppler assessment of the peak systolic velocity in the middle cerebral artery is now the standard to detect fetal anemia and determine the need for the first intrauterine transfusion. Assessment of the peak systolic velocity in the middle cerebral artery can be used to time the second transfusion, but its use to decide when to perform subsequent procedures awaits further study. New data suggest normal neurologic outcome in 94% of cases after intrauterine transfusion, although severe hydrops fetalis may be associated with a higher risk of impairment. Recombinant Rh immune globulin is on the horizon. Cell-free fetal DNA for fetal RHD genotyping may be used in the future to decide which patients should receive antenatal Rh immune globulin.