Fetal Anemia: Determinants and Perinatal Outcomes according to the Method of Intrauterine Blood Transfusion.

INTRODUCTION: Fetal anemia from hemolytic disease treated by intrauterine transfusion (IUT) can be performed by intraperitoneal, intracardiac, and intravascular transfusion (IVT). Objective of our study was to compare different transfusion techniques. METHODS: Retrospective review of IUT secondary to red cell alloimmunization was conducted at eight international centers from 2012 to 2020. Severe anemia suspected if middle cerebral artery peaks systolic velocity ≥1.5 multiples of the median. Demographic, delivery, and postnatal variables were analyzed. RESULTS: Total of 344 procedures, 325 IVT and 19 other techniques (non-IVT) included. No difference in demographics, history of stillbirth (20.5 vs. 15.8%, p = 0.7), prior pregnancy IUT (25.6 vs. 31.6%, p = 0.5) or neonatal transfusion (36.1 vs. 43.8%, p = 0.5). At first IUT, non-IVT had higher hydrops (42.1% vs. 20.4%, p = 0.03), lower starting hematocrit (13.3% [±6] vs. 17.7% [±8.2], p = 0.04), and trend toward lower gestational age (24.6 [20.1-27] vs. 26.4 [23.2-29.6] weeks, p = 0.08). No difference in birthweight, neonatal phototherapy, exchange, or simple transfusion was observed. CONCLUSION: This is one of the largest studies comparing techniques to treat fetal anemia. IVT was most performed, other techniques were more likely performed in hydrops, and lower starting hematocrit was seen. Neither technique affected outcomes. This study may suggest that physician's experience may be the strongest contributor of outcomes.

Prenatal management of fetal anemia due to pyruvate kinase deficiency: A case report.

BACKGROUND: Pyruvate Kinase (PK) deficiency is the most common enzyme defect of glycolysis, leading to congenital hemolytic anemia, which can occur during the neonatal period. STUDY DESIGN AND METHODS: We report the prenatal management of fetal anemia related to PK deficiency in a family with a severe proband. RESULTS: The couple had a first child born with hydrops, whose PK deficiency was diagnosed at 18 months of life. He was treated with allogeneic bone marrow transplantation. The second child was free from disease. For the third pregnancy, the amniocentesis revealed a PK deficiency. Weekly ultrasound monitoring of the middle cerebral artery velocity allowed the detection of severe fetal anemia. Two intrauterine red blood cell transfusions (IUTs) were performed, raising the fetal hemoglobin from 6.6 to 14.5 g/dl at 28 weeks' gestation and from 8.9 to 15.3 g/dl at 31 weeks. A hematopoietic stem cell allograft was discussed prenatally but not chosen, as it would not have significantly changed the perinatal prognosis. The patient delivered a 2730 g girl at 37 weeks, with hemoglobin of 13.6 g/dl. The child presented with neonatal jaundice treated with phototherapy and received postnatal transfusions. DISCUSSION: When a proband is identified in a family, fetal investigation is warranted, to set up third-trimester ultrasound surveillance and perinatal management. In case of fetal severe anemia of unknown etiology, the workup on fetal blood sampling before IUT should comprise the search for erythrocytes enzymopathies, such as PK deficiency. IUTs allow safer full-term delivery in cases with PK deficiency.

Potential Benefits of Bovine Colostrum in Pediatric Nutrition and Health.

Bovine colostrum (BC), the first milk produced from cows after parturition, is increasingly used as a nutritional supplement to promote gut function and health in other species, including humans. The high levels of whey and casein proteins, immunoglobulins (Igs), and other milk bioactives in BC are adapted to meet the needs of newborn calves. However, BC supplementation may improve health outcomes across other species, especially when immune and gut functions are immature in early life. We provide a review of BC composition and its effects in infants and children in health and selected diseases (diarrhea, infection, growth-failure, preterm birth, necrotizing enterocolitis (NEC), short-bowel syndrome, and mucositis). Human trials and animal studies (mainly in piglets) are reviewed to assess the scientific evidence of whether BC is a safe and effective antimicrobial and immunomodulatory nutritional supplement that reduces clinical complications related to preterm birth, infections, and gut disorders. Studies in infants and animals suggest that BC should be supplemented at an optimal age, time, and level to be both safe and effective. Exclusive BC feeding is not recommended for infants because of nutritional imbalances relative to human milk. On the other hand, adverse effects, including allergies and intolerance, appear unlikely when BC is provided as a supplement within normal nutrition guidelines for infants and children. Larger clinical trials in infant populations are needed to provide more evidence of health benefits when patients are supplemented with BC in addition to human milk or formula. Igs and other bioactive factors in BC may work in synergy, making it critical to preserve bioactivity with gentle processing and pasteurization methods. BC has the potential to become a safe and effective nutritional supplement for several pediatric subpopulations.

In utero treatment of severe fetal anemia resulting from fetomaternal red blood cell incompatibility: a comparison of simple transfusion and exchange transfusion.

OBJECTIVE: To compare in utero exchange transfusions (IUET) and in utero simple transfusions (IUST) for the treatment of fetal anemia resulting from red blood cell fetomaternal incompatibility. STUDY DESIGN: Retrospective comparative study from January 2006 through December 2011. The two techniques were compared for effectiveness, complications, and neonatal outcomes. RESULTS: 36 patients had 87 IUETs and 85 patients 241 IUSTs. Gestational age at the first transfusion was similar in both groups (IUET: 27±3.8 weeks; IUST: 27±4.7 weeks; NS) as was the initial fetal hemoglobin level (IUET: 6.4±2.8g/dL; IUST: 6.0±2.5g/dL; NS). No significant differences were noted for postprocedure complications or efficacy. The daily drop in hemoglobin level was similar in both groups (IUET: 0.41±0.23g/dL/day; IUST: 0.44±0.17g/dL/day; NS) as were the time intervals between two procedures. Gestational age at birth was earlier in the IUET group (34.4±1.3 weeks vs 35.5±1.8 weeks; p<0.001), but the postnatal transfusions or exchange transfusions rates and the duration of intensive phototherapy did not differ. No significant differences were noted for the overall survival rates (IUET: 100%; IUST: 96.4%; p>0.99). CONCLUSION: IUET does not appear to provide any benefits compared with IUST, neither to be associated with a higher complication rate. The choice of the technique depends on availability of packed blood cells with high hematocrit (70-80%).

Society for maternal-fetal medicine (SMFM) special report: the maternal-fetal medicine subspecialists' role within a health care system.

A maternal-fetal medicine (MFM) subspecialist has advanced knowledge of the medical, surgical, obstetrical, fetal, and genetic complications of pregnancy and their effects on both the mother and fetus. MFM subspecialists are complementary to obstetric care providers in providing consultations, co-management, or transfer of care for complicated patients before, during, and after pregnancy. The MFM subspecialist provides peer and patient education and performs research concerning the most recent approaches and treatments for obstetrical problems, thus promoting risk-appropriate care for these complicated pregnancies. The relationship between the obstetric care provider and the MFM subspecialist depends on the acuity of the maternal and/or fetal condition and the local resources. To achieve the goal of promoting early access and sustained adequate prenatal care for all pregnant women, we encourage collaboration with obstetricians, family physicians, certified midwives, and others, and we also encourage providing preconception, prenatal, and postpartum care counseling and coordination. Effective communication between all obstetric care team members is imperative. This special report was written with the intent that it would be broad in scope and appeal to a diverse readership, including administrators, allowing it to be applied to various systems of care both horizontally and vertically. We understand that these relationships are often complex and there are more models of care than could be addressed in this document. However, we aimed to promote the development of a highly effective team approach to the care of the high-risk pregnancy that will be useful in the most common models for obstetric care in the United States. The MFM subspecialist functions most effectively within a fully integrated and collaborative health care environment. This document defines the various roles that the MFM subspecialist can fulfill within different heath care systems through consultation, co-management, and transfer of care, as well as education, research, and leadership.

[Ten practical issues concerning acute poisoning with carbon monoxide in pregnant women]. / Dix questions pratiques concernant l'intoxication aiguë au monoxyde de carbone chez la femme enceinte.

BACKGROUND: The poisoning of carbon monoxide (CO) is the leading cause of death by poisoning in France. Its consequences are potentially serious to the fetus. Literature is ancient and little known. PURPOSE AND METHOD: Make an inventory of knowledge about carbon monoxide poisoning during pregnancy. RESULT: The CO causes maternal then fetal tissue hypoxia primarily by binding to hemoglobin with which it has a high affinity. Its transplacental passage may cause fetal harm, predominantly in the brain. Severity seems correlated with maternal symptoms during exposure. In the absence of maternal symptoms, however, the available data are reassuring. Hyperbaric oxygen therapy may reduce the risk to the fetus. DISCUSSION: Oxygen therapy should be offered in all cases of CO poisoning, especially if there are maternal symptoms during exposure. In addition, a fetal echography directed on the cephalic pole - even a fetal magnetic resonance imaging three weeks after exposure - should also be proposed.

Conservatively managed fetal goiter: an alternative to in utero therapy.

Fetal goiter may arise from a variety of etiologies including iodine deficiency, overtreatment of maternal Graves' disease, inappropriate maternal thyroid replacement and, rarely, congenital hypothyroidism. Fetal goiter is often associated with a retroflexed neck and polyhydramnios, raising concerns regarding airway obstruction in such cases. Prior reports have advocated for cordocentesis and intra-amniotic thyroid hormone therapy in order to confirm the diagnosis of fetal thyroid dysfunction, reduce the size of the fetal goiter, reduce polyhydramnios, aid with the assistance of maternal thyroid hormone therapy and reduce fetal malpresentation. We report two cases of conservatively managed fetal goiter, one resulting in a vaginal delivery, and no evidence of postnatal respiratory distress despite the presence of polyhydramnios and a retroflexed neck on prenatal ultrasound.

Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida.

OBJECTIVE: Neural stem cells (NSCs) may promote spinal cord repair in fetuses with experimental spina bifida. We sought to determine the fate of amniotic-derived NSCs (aNSCs) after simple intra-amniotic injection in a syngeneic model of spina bifida. METHODS: Fetal neural tube defects were induced on 20 pregnant Lewis dams by prenatal administration of retinoic acid. Ten dams served as amniotic fluid donors for epigenetic isolation of aNSCs, which were expanded and labeled with 5-bromo-2'-deoxyuridine. The remaining 10 dams received intra-amniotic injections of the processed aNSCs, blindly in all their fetuses (n = 37) on gestational day 17 (term = E21-22). Fetuses with spina bifida underwent screening for the presence of donor aNSCs in the spinal cord at term. RESULTS: Donor cells were identified in 93.3% of the animals with spina bifida, selectively populating the neural placode, typically in clusters, retaining an undifferentiated morphology, and predominantly on exposed neural surfaces, though some were detected deeper in neighboring neural tissue. CONCLUSIONS: The amniotic cavity can serve as a route of administration of NSCs in experimental spina bifida. Simple intra-amniotic delivery of NSCs may be a practical adjuvant to regenerative strategies for the treatment of spina bifida.

A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.

PURPOSE: Meconium ileus (MI) is the earliest clinical manifestation of cystic fibrosis (CF), occurring in up to 20% of patients with CF. Our aim was to review and integrate current knowledge about the diagnosis and management of fetuses and neonates with MI that may aid the pediatric surgeon in caring for these patients. METHODS: We identified areas of interest including pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis. We performed a Medline search using the search term meconium ileus for English language articles published in the last 20 years. We reviewed reference lists to identify other articles of historical significance. RESULTS: Meconium ileus is primarily associated with CF transmembrane (conductance) regulator mutations F508del, G542X, W1282X, R553X, and G551D, and modifier genes have been found to explain approximately 17% of the phenotypic variability. Mouse, pig, and ferret models for CF demonstrate neonatal bowel obstruction mimicking MI. Sonographic findings of hyperechoic masses and dilated bowel in a high-risk fetus are suggestive of MI. Less than 7% of low-risk fetuses with hyperechoic bowel will have MI. Contemporary series of noninvasive management with Gastrografin enema report success rates of 36% to 39%, significantly lower than historical values. The optimal surgical technique remains controversial, although primary anastomosis results in surgical complication rates between 21% and 31%, higher than those noted with delayed anastomosis. Pulmonary function for patients with CF and MI at 15 and 25 years old is similar to those without MI, although height and weight percentiles may be lower. CONCLUSIONS: This review for pediatric surgeons presents an examination of the literature and synthesizes current information about the pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis of the patient with CF and MI.

Clinical trials during pregnancy: what has been done.

OBJECTIVE: We describe clinical trials conducted in pregnant women. METHODS: We searched PubMed database for articles related to clinical trials between 01/01/2000 and 31/12/2009 involving pregnant women by using the preferred terms "pregnancy", "human", and "clinical trials". RESULTS: Of 1,264 retrieved publications, 762 (60%) were excluded, leaving 502 for analysis: 53% were preventive studies in maternal or fetal conditions; 47% were therapeutic trials, mostly focused on acute obstetric diseases; 66% were assigned a pharmacological intervention. The studied drugs were 16% for labour induction and 15% for abortive procedures, followed by multivitamins and micronutrients, labour analgesia and anesthesia, antibiotics, tocolytics, and antimalarial drugs. The main objectives of the studies were focused on efficacy (54%) and efficacy and safety (26%); 81% of the studies were controlled, randomized and parallel-design trials; 19% were blinded. CONCLUSION: Clinical trials in pregnant women are mainly conducted with an efficacy objective regarding maternal-fetal prevention and in obstetric diseases to study labor induction and abortive measures. This is in line with the type of intervention and drugs involved.

Fetal intraperitoneal injection of immunoglobulin diminishes alloimmune hemolysis.

We report a case of severe fetal anemia associated with maternal anti-M antibody that was treated by direct injection of pooled human immunoglobulin into the fetal abdominal cavity. Four treatments at a dosage of 2 g per-kg estimated fetal body weight were performed, and no side effects were observed. A healthy baby girl was delivered transvaginally at 38 weeks, with neither exchange transfusion nor phototherapy required. Follow-up over 12 months found no indications of anemia or developmental delay in the child. This is believed to be the first report of fetal anemia in a blood-type-incompatible pregnancy being treated successfully with only direct immunoglobulin injection into the fetus. The immunoglobulin may have functioned as a neutralizing antibody causing the anemia to improve.

Management of anti-Jka alloimmunization.

OBJECTIVE: To determine whether prenatal management using guidelines established for anti-D is applicable to anti-Jka. STUDY DESIGN: A computerized database containing the records of all alloimmunized pregnancies at The Ohio State University Medical Center with due dates from 1959 to 2008 was used to identify pregnancies affected only by anti-Jka. Only cases with evidence that the newborn was Jka antigen positive were included. RESULTS: Twenty affected pregnancies met inclusion criteria. Of those, 16 pregnancies required monitoring with serum titers only and 4 were followed with more diagnostic tests as recommended during that time period. One pregnancy with the highest titer of 32 and elevated middle cerebral artery peak systolic velocity (MCA PSV) required 4 intrauterine transfusions for fetal anemia. Another pregnancy with a titer of 32 had an infant who required phototherapy for hemolytic disease of the fetus/newborn (HDFN), with a hemoglobin value of 15.9 g/dL. None of the other 18 infants required any therapy for HDFN. CONCLUSION: Our case series identified severe disease in 1 of 20 pregnancies from anti-Jka using maternal antibody titer and MCA PSV. Criteria used for monitoring RhD alloimmunization were effective in detecting severe HDFN resulting from to anti-Jka.

Pediatric arrhythmias: which are the news?

Knowledge about cardiac arrhythmias has significantly improved in the last 20 years, and the improvements in diagnosis and in therapy have also had important effects on the management of pediatric arrhythmias. In this paper, the most important developments in the field of management of pediatric arrhythmias (fetal arrhythmias, genetics, pharmacological strategies, radiofrequency ablation, new technologies) as well as the remaining problems (risk stratification of some arrhythmic forms as for example Wolff-Parkinson-White and ventricular arrhythmias) will be discussed.

[The Italian law on termination of pregnancy (194/1978). Should it be revised? The palliative care option]. / Terapia palliativa del feto/neonato con malformazioni incompatibili con la vita: una opzione alternativa alla interruzione di gravidanza.

The section of the Italian law on the termination of pregnancy (no. 194/1978) regarding late termination is revised and discussed in the light of the various options that could be offered to parents. Besides recent suggestions to apply time limits, the author reviews an alternative therapeutic option, considered the only feasible revision of the law which calls for strong involvement by the neonatologist and close collaboration with the obstetrician: the offer of palliative care for foetus/neonate and parents.

Defining standards of care in maternal-fetal medicine.

OBJECTIVE: The purpose of this study was to describe current practice patterns for 7 controversial topics in Maternal-Fetal Medicine. STUDY DESIGN: An interactive survey of obstetric treatment was performed as part of a postgraduate course at the 2004 Annual Meeting of the Society for Maternal-Fetal Medicine. Seven controversial topics were addressed, which included tocolytic therapy, progesterone supplementation for the prevention of preterm birth, screening for inherited thrombophilia, cervical cerclage for a shortened cervix, treatment of preterm premature rupture of membranes, magnesium sulfate seizure prophylaxis, and dexamethasone therapy for HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. RESULTS: A total of 298 obstetric care providers attended the postgraduate course. By report, most attendees were maternal-fetal medicine specialists (60.7% of respondents) who were >10 years out from specialty training (56.3% of respondents) and who were practicing in a university-based setting (52.9% of respondents). An average of 233 practitioners (range, 157-298 practitioners) answered each question. An analysis of the responses allowed for the determination of current practice patterns in the 7 controversial areas addressed. CONCLUSION: Contemporary practice patterns for 7 controversial topics in obstetric medicine are described. Such surveys may be useful in defining standards of care in maternal-fetal medicine.

Rapidly polymerizing hydrogel prevents balloon dislodgement in a model of fetal tracheal occlusion.

BACKGROUND/PURPOSE: This study examined whether an injectable hydrogel could buttress the balloon used in fetal tracheal occlusion, thus preventing its displacement. METHODS: Fetal lambs (n = 11) underwent tracheal occlusion through local delivery of a detachable silicone balloon and were divided in 2 groups: group I had no further manipulations, and group II received an intratracheal injection of a rapidly polymerizing hydrogel, cranially to the balloon. Near term, balloon placement was examined, the lung volume-to-body weight ratio (LV:BW) was determined, and tracheal histology was performed. Statistical analysis was by the Fisher's Exact test, with significance set at P <.05. RESULTS: Complete tracheal occlusion was achieved in all fetuses intraoperatively. The rate of balloon dislodgement was significantly higher in group I (4 of 7, or 57.1%) than in group II (0 of 4). In group II, balloons were recovered in situ with a column of residual hydrogel reinforcing their cephalad position. Animals in which balloon occlusion was maintained had significantly higher LV:BW, with no evidence of tracheal damage. CONCLUSIONS: Intratracheal delivery of a rapidly polymerizing hydrogel cephalad to detachable silicone balloons results in improved fetal tracheal occlusion, with no harmful effects to the trachea. This adjuvant principle may enhance minimally invasive balloon tracheal occlusion for treatment of severe fetal pulmonary hypoplasia.

Pulmonary structural maturation and pulmonary artery remodeling after reversible fetal ovine tracheal occlusion in diaphragmatic hernia.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with thickened pulmonary arteries (PA) contributing to pulmonary hypertension. In the current study, the effects of antenatal glucocorticoids and reversible tracheal occlusion (TO) on PA structure were assessed in a hypoplastic lung model. METHODS: A left-sided CDH was created in fetal lambs at 80 days gestation, TO at 108 days, and release of the occlusion (TR) at 129 days. All were given 1 dose of maternal glucocorticoids at 135 days. At 136 days (term, 145 days), the fetus was delivered by cesarian section. CDH (n = 7), CDH + TO (n = 6), CDH + TO + TR (n = 6), and unoperated twin controls (n = 16) were compared. Outcome measurements were (1) lung growth, represented by lung weight to body weight ratio (LW/BW), (2) lung structural maturation, which is inversely proportional to mean terminal bronchiole density (MTBD), (3) PA medial and adventitial areas (square micrometers), (4) lung capillary load, which is the ratio of vessel surface area (SA) to tissue SA ratio. RESULTS: CDH lungs were hypoplastic with a low LW/BW and high MTBD. The small PAs (<75 microm) of CDH had an increased medial area, indicating increased muscle mass and an increased adventitial area. CDH + TO +/- TR increased LW/BW and achieved normal structural lung maturity with a low MTBD. Only CDH + TO thinned the PA medial area closer to control values. The adventitial area remained thick in CDH +/- TO +/- TR when compared with controls. All 4 groups had similar capillary load. CONCLUSIONS: TO may be especially important for PA remodeling in the latter part of gestation, because TR 1 week before delivery prevents thinning of the small PAs in CDH. The shaping achieved by TO in terms of lung growth, structural maturity, and pulmonary artery medial area thinning may prove beneficial in lessening the severity of the associated pulmonary hypertension in CDH.

Autologous placental blood transfusion after a planned neonatal pacemaker implantation.

A fetal third-degree atrio-ventricular block was diagnosed in a 22-year-old woman at 24 weeks of gestation. During clinical follow-up a mild to moderate tricuspid regurgitation was detected at 35 weeks and maternal connective tissue diseases were excluded. Early postnatal cardiac pacing therapy was planned and autologous placental blood transfusion was proposed for the treatment of probable blood loss due to pacemaker implantation. A male infant was delivered at 38 weeks vaginally and 87 mL of placental blood was collected from the undelivered placenta. The placental blood was negative for viral markers and syphilis. Subsequent tests for bacteriological cultures were also negative. Within 6 h of delivery, the baby underwent cardiac pacemaker implantation and received 45 mL of autologous placental blood. Autologous placental blood transfusion was successfully used for the treatment of predicted blood loss after a planned neonatal surgical procedure.

Percutaneous laser ablation of fetal congenital cystic adenomatoid malformation: too little, too late?

OBJECTIVE: Congenital cystic adenomatoid malformation, type III (CCAM III) lesions are large, bulky tumors which can cause mediastinal shift, prevent normal pulmonary growth, and compress the esophagus, thus leading to complications of nonimmune hydrops, pulmonary hypoplasia and polyhydramnios. Because the mortality rate of untreated fetuses with CCAM and hydrops is high, early delivery or intrauterine resection of the enlarged pulmonary lobe (lobectomy) is indicated; however, open fetal resection of CCAM at less than 30 weeks is associated with perioperative mortality that approaches 40%, as well as the usual maternal and fetal morbidity of open fetal surgery. As an alternative, percutaneous laser ablation of a CCAM III lesion with hydrops was attempted. METHODS: A 30-year-old G3 P1011 with CCAM III in the left fetal hemithorax developed mediastinal shift, hydrops and polyhydramnios at 23 weeks' gestation. After pregnancy termination and open fetal resection were declined, an 18-gauge needle was placed into the fetal tumor percutaneously under real-time ultrasonographic guidance, using sterile technique with light sedation. A cleaved 400-microm Nd:YAG laser fiber was passed through the needle lumen, and using a power setting of 15 W, a total of 2,943 J of laser energy was delivered in pulses of 1.0 s at 0.2-second intervals over two sessions one week apart. RESULTS: Although tumor size decreased, the hydrops worsened and fetal death occurred. CONCLUSIONS: The fetus with CCAM complicated by hydrops is already so compromised by the advanced state of the disease that insufficient time is available for necrotic tissue reabsorption after minimally invasive therapy with laser energy. Until earlier markers for intervention are determined, percutaneous laser debulking of CCAM is unlikely to be successful.

Gene therapy: clinical considerations.

Gene therapy can be defined as the introduction of nucleic acid into cells to ameliorate a disease process. To date there have been more than 313 trials with more than 2000 patients enrolled. The majority of these trials are Phase I or Phase II and have target diseases of either cancer or acquired immunodeficiency syndrome using retroviral and retroviral vectors. The choice of molecular target and the means of delivery have varied and chosen on the basis of the specific indication. Until recently the risks associated with treatment had been under appreciated. The first fatality associated with gene therapy occurred in September 1999 in which an adenoviral vector was used in the treatment of a patient with ornithine transcarbamylase deficiency. Subsequent to this report, other reports have surfaced suggesting that reporting of previous non-fatal reactions may have been minimized. Safety must be considered in relation to the disease process and to alternative treatments available. It may be easier to rationalize placing patients at risk who are facing a fatal disease process without effective alternative therapies. The ultimate goal of gene therapy will be the injection of a vector that has a specific target cell and that will be regulated by physiologic signals. Such a goal will require major improvements in the currently available delivery systems or the development of novel vectors.