The downside to restricting the procedure to trial sites is that surgeons elsewhere can’t continue to develop safer, less invasive techniques for what Harrison describes as another difficult open procedure. But, he adds, “if we didn’t organize a trial now, thousands of patients would have had the surgery without our ever knowing whether it’s beneficial. And then you’d never be able to persuade women to join a trial.”

Whatever the outcome of the NIH study, surgery at 22 weeks’ gestation comes too late to prevent many lifelong problems, Alan Flake of Philadelphia says. For the past 20 years, the pediatric surgeon has been researching other kinds of fetal interventions, involving stem cells and gene therapy. Now working on rats, Flake treats spina bifida by injecting a scaffolding material containing mesenchymal stem cells, found in bone marrow, around the spinal defect in the fetus. The stem cells then form bone, cartilage and skin. “We think you can inject this stuff much earlier than you can operate,” Flake says.

But the real test case for introducing stem cells to human fetuses is likely to be sickle cell anemia, says Flake, who expects human experiments to begin in about five years. “And if we succeed with sickle cell disease, we’ll potentially be able to use stem cell therapy for any disease now treated with bone marrow transplants, assuming we can diagnose the disease early in gestation,” he says.

Fisk of the University of Queensland has had success using fetal stem cells to cure the bone disease osteogenesis imperfecta in mice, and in Sweden doctors have transplanted stem cells derived from a fetal liver into a fetus diagnosed with the disease. “I’m not sure the procedure was done correctly, but there is evidence that the child has fewer fractures than if there had been no fetal transplant,” Flake says.

There is yet another frontier for fetal intervention: gene therapy. Although treatments in adults have been beset with problems, Flake says that during the past five years, phenomenal advances have made it safer. He predicts that gains in decoding the genetic basis for disease will mean that within 10 to 15 years, “we’ll be able to detect 100% of known genetic abnormalities in fetuses,” allowing doctors to intervene in utero to prevent a disease that would appear in childhood or adulthood. “We’re pretty excited about fetal therapy for anticipated diseases,” Flake says. “We already know how to transfer genes into a stem cell in utero. So potentially we can reverse a genetic predisposition to, say, breast cancer.”

“Stem cell and gene therapy will open a world of things we can treat in the fetus,” says Johnson. “Still, there will always be a role for surgery. TTTS, for example, is a physical abnormality that can’t be fixed with stem cells. So our goal is to make surgery as minimally invasive to mother and fetus as possible. In the past eight years, our scopes and sheaths halved in diameter. And today, our laser procedure involves only a 24-hour admission. Ten years from now, people will look at the procedures we do today and say, ‘You did what?’

  Dossier

1. “The University of California at San Francisco Fetal Treatment Center: A Personal Perspective,” by Michael R. Harrison, Fetal Diagnosis and Therapy, Issue 19, 2004. The acknowledged father of fetal surgery details his triumphs and failures in pioneering the field and offers a candid report card on its current state.

2. “Toward the Ethical Evaluation and Use of Maternal-Fetal Surgery,” by Anne Drapkin Lyerly, Elena A. Gates, Robert C. Cefalo and Jeremy Sugarman, Obstetrics & Gynecology, October 2001. An exploration of the ethical issues that arise when healthy women and their fetuses are exposed to highly experimental procedures.

3. “The Twin-Twin Transfusion Syndrome: Spectrum of Cardiovascular Abnormality and Development of a Cardiovascular Score to Assess Severity of Disease,” by Jack Rychik, Zhiyun Tian, Michael Bebbington et al., The American Journal of Obstetrics & Gynecology, October 2007. Researchers at the Children’s Hospital of Philadelphia detail their development of a score using fetal echocardiography to precisely assess the severity of twin-twin transfusion syndrome cases.

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