Seminars in Fetal & Neonatal Medicine

Title Page/Aims and Scope/Editorial Board

2010-02-01

Open fetal surgery for life-threatening fetal anomalies

N. Scott Adzick — 2009-06-19

Summary: After more than two decades of experimental and clinical work, fetal surgery is an accepted treatment option for highly selected fetuses with life-threatening anomalies. Fetal lung masses associated with hydrops are usually fatal. These lesions can be resected in utero if they are predominantly solid or multicystic. Fetal sacrococcygeal teratoma complicated with progressive high output cardiac failure may benefit from in-utero resection of the tumor. Important lessons have been learned about perioperative management and maternal, fetal, and neonatal outcomes after open fetal surgery.

Fetal myelomeningocele: Natural history, pathophysiology, and in-utero intervention

N. Scott Adzick — 2009-06-19

Summary: Myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. In-utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. It is estimated that about 400 fetal operations have now been performed for MMC worldwide. Despite this large experience, the technique remains of unproven benefit. Preliminary results suggest that fetal surgery results in reversal of hindbrain herniation (the Chiari II malformation), a decrease in shunt-dependent hydrocephalus, and possibly improvement in leg function, but these findings might be explained by selection bias and changing management indications. A randomized prospective trial (the MOMS trial) is currently being conducted by three centers in the USA, and is estimated to be completed in 2010. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in-utero intervention.

Twin-to-twin transfusion syndrome: current understanding of pathophysiology, in-utero therapy and impact for future development

Michael Bebbington — 2009-06-19

Summary: Whereas monochorionic twins account for only 30% of twin gestations, they contribute to a disproportionate extent to the overall twin perinatal morbidity and mortality. Twin-to-twin transfusion syndrome can occur at any point in a monochorionic gestation but is associated with significant increases in both morbidity and mortality when it develops before 26 weeks of gestation. It is still not possible to predict accurately those pregnancies that will be affected. This has resulted in the practice of routine ultrasound surveillance beginning at the end of the first trimester. Our understanding of the physiology still has many gaps but there is an increased recognition of the heterogeneity that exists especially in the early stages of the disease. The role of the cardiovascular response of the recipient twin offers the potential for further refining the application of our current treatment modalities and may offer insight into future therapies. The optimal therapy at this point in time resides clearly with selective laser photocoagulation, and further refinements of techniques and patient selection may continue to improve outcomes. Finally, the in-utero responses generated by the fetuses to the physiologic stress of twin-to-twin transfusion may influence their response or ability to respond to cardiovascular stress in later life. If there is in-utero programming, then the detection and timely treatment of conditions such as twin–twin transfusion syndrome may have lifelong implications for both members of the twin pair.

Management of prenatally diagnosed congenital diaphragmatic hernia

Holly L. Hedrick — 2009-11-02

Summary: Congenital diaphragmatic hernia (CDH) is a congenital anomaly that presents with a broad spectrum of severity dependent upon components of pulmonary hypoplasia and pulmonary hypertension. While advances in neonatal care have improved the overall survival of CDH in experienced centers, mortality and morbidity remain high in a subset of CDH infants with severe CDH. The most important prenatal predictor of outcome in left-sided CDH is liver position. More precise and reproducible prenatal predictive parameters need to be developed to allow standardization of results between centers and appropriate design of clinical trials in CDH. Thus far, all randomized trials comparing prenatal intervention to standard postnatal therapy have shown no benefit to prenatal intervention. Although recent non-randomized reports of success with balloon tracheal occlusion (and release) are promising, prenatal therapy should not be widely adopted until a well-designed prospective randomized trial demonstrating efficacy is performed. The increased survival and subsequent morbidity of CDH survivors has resulted in the need to provide resources for the long-term follow-up and support of the CDH population.

Fetal thoracic and bladder shunts

Stephanie Mann, Mark P. Johnson, R. Douglas Wilson — 2009-07-14

Summary: Congenital obstructive lesions involving the bladder and the lung can lead to serious complications for the newborn. The in-utero placement of a diverting shunt in the fetal bladder or thoracic cavity can decrease the morbidity and mortality associated with these obstructive conditions. This review focuses on the indications for prenatal evaluation, technique, and outcomes for those fetuses with a lower urinary tract obstruction, congenital pleural effusion or macrocystic congenital cystic adenomatoid malformation after placement of a vesicoamniotic or thoracoamniotic shunt.

Ex-utero intrapartum therapy

Kenneth W. Liechty — 2009-08-17

Summary: The ex-utero intrapartum therapy (EXIT) procedure was designed to secure the airway at delivery in fetuses who had undergone tracheal occlusion for severe congenital diaphragmatic hernia. The EXIT was then adapted for deliveries where the airway may be difficult to secure, such as large neck masses or congenital high airway obstruction. Subsequently, use of EXIT has been extended to fetal anomalies where resuscitation may be compromised, including large thoracic masses, severe congenital diaphragmatic hernia, or pulmonary agenesis. The key to EXIT is preservation of uteroplacental blood flow and gas exchange, using inhalational agents to provide uterine relaxation, and maintenance of uterine volume by amnioinfusion and only partial exposure of the fetus. This provides time for procedures such as laryngoscopy, bronchoscopy, vascular access, resection of neck or lung masses, or cannulation for extracorporeal membrane circulation, in order to convert an emergent crisis to a controlled situation.

Anesthesia for fetal surgery

Kha M. Tran — 2009-06-22

Summary: Fetal surgery pushes the limits of knowledge and therapy beyond conventional paradigms by treating the developing fetus as a patient. Providing anesthesia for fetal surgery is challenging for many reasons. It requires integration of both obstetric and pediatric anesthesia practice. Two patients must be anesthetized for the benefit of one, and there is little margin for error. Many disciplines are involved, and communication must be effective. Conducting anesthetic research with vulnerable populations, such as pregnant women and their fetuses, is difficult, and many questions remain unanswered. Work must be done in the study of possible neurotoxicity caused by exposure of developing brain to anesthetic agents. The effects of stress on the developing fetus must also be further examined. Optimal anesthetic regimens remain to be determined.

Stem cell and genetic therapies for the fetus

Jessica L. Roybal, Matthew T. Santore, Alan W. Flake — 2009-06-22

Summary: Advances in prenatal diagnosis have led to the prenatal management of a variety of congenital diseases. Although prenatal stem cell and gene therapy await clinical application, they offer tremendous potential for the treatment of many genetic disorders. Normal developmental events in the fetus offer unique biologic advantages for the engraftment of hematopoietic stem cells and efficient gene transfer that are not present after birth. Although barriers to hematopoietic stem cell engraftment exist, progress has been made and preclinical studies are now underway for strategies based on prenatal tolerance induction to facilitate postnatal cellular transplantation. Similarly, in-utero gene therapy shows experimental promise for a host of diseases and proof-in-principle has been demonstrated in murine models, but ethical and safety issues still need to be addressed. Here we review the current status and future potential of prenatal cellular and genetic therapy.

The North American Fetal Therapy Network (NAFTNet): a new approach to collaborative research in fetal diagnosis and therapy

Mark Paul Johnson, on behalf of NAFTNet — 2009-06-26

Summary: In August 2004, the National Institutes of Health organized a ‘Workshop on Fetal Therapy’ to develop a plan for the maternal–fetal, surgical, and neonatal evaluation and treatment of pregnancies that might benefit from in-utero therapy. At the completion of the workshop several recommendations were made, foremost of which was the ‘formation of a cooperative group of clinical investigators to help set a national agenda for research and clinical progress in the field of fetal therapy’. Somewhat by coincidence, a multidisciplinary ‘Fetal Therapy Working Group’ that had been formed earlier in the year was well-positioned to accept this national mandate and proposed development of a North American Fetal Therapy Network (NAFTNet) to foster collaborative research between active fetal diagnosis and treatment centers in both the USA and Canada, develop a peer review mechanism for study proposals, explore ways to centralize data collection and study development, and establish an educational agenda for medical professionals and the public as well as training of future leaders in the field. NAFTNet represents a new paradigm and approach to international collaborative research. Early success has resulted in the recognition of the power of collaborative research efforts in studying rare congenital anomalies and intervention strategies to improve outcomes and survivals in such limited populations. By abandoning ‘competitive research’ for a cooperative, collaborative environment of research partnership, NAFTNet strives to be more responsible and effective in using limited resources and improving care for pregnancies and children born with congenital anomalies.

Fetal surgery is a clinical reality

2009-11-16

Summary: An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable to fetal surgical intervention. We discuss the current clinical status and recent advances in endoscopic and open surgical interventions. In Europe, fetoscopic interventions are widely embraced, whereas the uptake of open fetal surgery is much less. The indications for each access modality are different, hence they cannot substitute each other. Although the stage of technical experimentation is over, most interventions remain investigational. Today there is level I evidence that fetoscopic laser surgery for twin-to-twin transfusion syndrome is the preferred therapy, but this operation actually takes place on the placenta. In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele. Overall maternal safety is high, but rupture of the membranes and preterm delivery remain a problem. The increasing application of fetal surgery and its mediagenicity has triggered the interest to embark on fetal surgical therapy, although the complexity as well as the overall rare indications are a limitation to sufficient experience on an individual basis. We plead for increased exchange between high volume units and collaborative studies; there may also be a case for self-regulation. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience.

Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial

Luc Cornette — 2009-11-30

In this prospective, multi-center, double-blind, placebo controlled, randomized trial, the authors investigate whether bovine lactoferrin (BLF) can reduce the incidence of late-onset sepsis in VLBW neonates. BLF is a milk glycoprotein involved in innate immune host defenses, and may have antimicrobial and immunomodulation activities (decreasing TNF-α production), as well as promoting a mature and healthy gut. Between October 2007 and July 2008, 472 VLBW infants are randomly assigned to receive the following additive from birth until day 30 (1000 - 1500g) or day 45 (< 1000g) of life: