What's the best way to treat twin-twin transfusion syndrome?

It's one of the biggest controversies in fetal surgery and the cause of heated debate among surgeons and maternal-fetal medicine physicians around the world: What's the best way to treat twin-twin transfusion syndrome (TTTS), one of the most common conditions requiring fetal surgery and the leading cause of mortality in twins?

The benchmark, NIH-funded study on TTTS, conducted at 17 centers in the United States, was presented at the annual meeting of the Society for Maternal-Fetal Medicine in San Francisco, and it won't likely resolve the question of which is the best procedure. The study, led by Timothy Crombleholme, M.D., director of the Fetal Care Center of Cincinnati, shows that the question isn't which surgical procedure is better, it's when the procedure is done.

Dr. Crombleholme issued a clarion call to fetal care specialists around the world. "The earlier in gestation TTTS is diagnosed, the more severe the syndrome tends to be," says Dr. Crombleholme, who is also a pediatric surgeon at Cincinnati Children's Hospital Medical Center. "We have to shift attention to diagnosing this earlier in the progression of the syndrome and being more aggressive about intervention. We can't conclude that one therapy is better than another, but it's apparent that we're going to compromise survival if treatment isn't initiated before it gets to be severe."

In TTTS, the way in which blood flows through the connecting blood vessels on a shared placenta is unequal. As a result, the donor twin has slowed growth and decreased amniotic fluid, while the recipient has too much amniotic fluid and develops a form of heart failure. Without treatment, TTTS is fatal for at least 90 percent of twins, and both twins are at risk for severe complications.

There are two main treatment modalities: amnioreduction, in which excess amniotic fluid is removed from the recipient twin, or a fetoscopic laser procedure to treat the anatomic basis for the syndrome. Until now, the only major study comparing these two treatments for TTTS was the Eurofetus trial, which compared laser and amnioreduction as primary therapies. That study, published in The New England Journal of Medicine in 2004, found that, at six months, there was better survival among twins using laser vs. amnioreduction.

The NIH-funded study, which began in 2002, required participants to have more severe disease and to have already failed an initial amnioreduction. But when the Eurofetus results were published, everyone thought that laser was superior and stopped referring patients. The American investigators asked that the trial be stopped. Unbeknownst to investigators at that time, the trial oversight committee found significant differences between the two treatment modalities and recommended that the trial be stopped, which it was in May of 2005.

The trial had uncovered higher mortality among recipient twins who received laser treatment. But overall, survival of one or both twins of the same pregnancy was no different between the two treatments. In addition, there was no difference between survival rates of donor twins and recipient twins. How is this possible?

"It turns out that in amnioreduction, there were significant numbers of treatment failures, so patients were dropping out in the amnioreduction arm because they were failing therapy, whereas they were dying in the laser therapy," says Dr. Crombleholme. Statistically, these patients are considered to have had the same outcome: a treatment failure. So, ultimately, there was no significant difference in survival of one or both twins between the two treatments."

What Dr. Crombleholme and his colleagues did find were two predictors of success. One was the stage of severity of TTTS. The other was the echocardiographic findings of heart failure. Fetal echocardiography, which is not done routinely in TTTS in most centers, should be done whenever a patient is diagnosed, according to Dr. Crombleholme

"While one cannot conclude from this study that one therapy is better than the other, neither can one conclude that they're equivalent, because it included patients who failed an initial amnioreduction and then went on to get laser," says Dr. Crombleholme.