The Health Daily

Researchers are reporting that they have developed a new way to help doctors and parents make some of the most agonizing decisions in medicine, about how much treatment to give tiny, extremely premature infants.

These are infants at the edge of viability, weighing less than 2.2 pounds and born after 22 to 25 weeks of pregnancy, far ahead of the normal 40 weeks. About 40,000 babies a year are born at this very early stage in the United States.

The new method uses an online calculator developed for such cases factoring in traits like birth weight and sex and generating statistics on chances of the baby’s survival and the likelihood of disabilities (www.nichd.nih.gov/neonatalestimates).

The statistics are not a personal prediction. They estimate risk based on data from similar infants in a large study being published on Thursday in The New England Journal of Medicine.

Certain factors gave babies an advantage. At any given gestational age, they were more likely to survive and escape serious disability if they weighed more than others, if they were singletons rather than twins or multiples or if their mothers had been given steroids before birth to help the fetal lungs to mature.

Girls also fared better than boys of the same age, a factor doctors have known a long time without being able to explain.

Any of those factors was about as good as being a week older, which makes an enormous difference in development from 22 to 25 weeks’ pregnancy, the researchers said. The finding means that a girl at 23 weeks could be as strong as a boy at 24.

“If you could take what the girls have and give it to the boys, we’d be one step ahead of the game,” said Dr. Rosemary D. Higgins, an author of the study and a program scientist at the Neonatal Research Network of the National Institute of Child Health and Human Development.

Although some extremely premature infants do well, many die, sometimes after weeks or months of painful invasive procedures in the intensive care unit. Survivors often suffer brain damage, behavior problems, vision and hearing loss and other disabilities.

Outcomes are nearly impossible to predict at birth. Doctors and parents struggle to decide when aggressive treatment seems reasonable — and when death or severe disability seems so likely, even with treatment, that it would be kinder to avoid painful procedures and provide just “comfort care,” letting nature take its course and letting the child die.

These decisions, made every day in hospitals around the country, are “heart wrenching and passionate,” Dr. Higgins said. “No one ever thinks they’re going to be in this situation, and it’s difficult, for families and also for physicians.”

Dr. Higgins said the study and the calculator were part of an effort to give doctors and parents more solid evidence to make decisions. She said people might be misled by occasional reports of tiny “miracle babies” who beat the odds and wrongly imagined high rates of survival and good health.

Dr. Higgins said she had no idea what overall effect the study and calculator might have on medical practice or whether they would lead to more or less treatment of extremely premature infants. Two families in the exact same situation could easily make opposite decisions about whether to pursue treatment.

Currently, decisions about using respirators, intravenous feeding and other forms of intensive care are mostly based on estimates of a baby’s gestational age — how far along the pregnancy was. Intensive care is often given to infants born in the 25th week, but not the 22nd. The hardest judgment calls are for babies in the 23rd and 24th weeks.

Plugging numbers into the calculator shows that two infants with the same gestational age, the usual criterion to decide treatment, can have quite different odds of survival and disability.

For instance, a 24-week-old two-pound male twin whose mother did not receive steroids has survival odds of 69 percent and a 50 percent chance of having a severe impairment. A female twin the same age and weight has survival odds of 86 percent and a 23 percent chance of severe impairment.

In theory, at least, the calculator would seem to favor treating girls, because, all else being equal, their odds for survival are better.

The study included 4,446 infants born at 22 to 25 weeks at 19 hospitals in the Neonatal Research Network; 744, generally the smallest and most premature, did not receive intensive care, and all died. The babies were assessed at birth, and the survivors were examined again shortly before turning 2.

Over all, half the infants died, half the survivors had neurological impairments, and half the impairments were severe.

Many survivors spent months in the hospital, at a typical cost of $3,400 a day. The researchers estimated that if all babies born at 22 to 23 weeks received intensive care, for every 100 infants treated there would be 1,749 extra hospital days and zero to nine additional survivors, with zero to three having no impairment.

Dr. Eric C. Eichenwald, medical director of the newborn center at Texas Children’s Hospital in Houston, said that the study was important and that its most striking finding was how large the benefits of the various factors could be.

Dr. Eichenwald said the calculator was “a way in which we can provide more accurate information to the process of counseling parents as to what the burdens of intensive care might be.”

Dr. Nehal A. Parikh, another author of the study, from the University of Texas Medical School at Houston, said he thought the statistics would help doctors in advising families.

“We lay out the facts, rather than our own opinions,” Dr. Parikh said, “because we’re not the ones taking these babies home.”

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When cold medicine containing a poison made in China killed nearly 120 Panamanians in 2006 and early 2007, Americans could take some comfort in the belief that a similar epidemic could never happen here, not with one of the best drug regulatory systems in the world.

Then last spring, hundreds if not thousands of pets died or were sickened in the United States by a Chinese pet food ingredient that contained lethal levels of melamine, an industrial product used to artificially boost protein levels. That was followed quickly by the discovery that Americans were brushing their teeth with Chinese toothpaste containing a poisonous chemical used in antifreeze.

Still, no Americans died from the chemical.

And then came heparin.

A hugely popular blood thinner used in surgery and dialysis, heparin turned out in some cases to contain a mystery substance that sophisticated lab tests earlier this month determined to be a chemically modified substance that mimics the real drug. The United States Food and Drug Administration has linked it to 19 deaths and hundreds of severe allergic reactions, though the agency is still investigating whether the contaminant was the actual cause.

What a difference a year makes.

After many near misses and warning signs, the heparin scare has eliminated any doubt that, here and abroad, regulatory agencies overseeing the safety of medicine are overwhelmed in a global economy where supply chains are long and opaque, and often involve many manufacturers.

“In the 1990s governments were all about trying to maximize the volume of international trade,” said Moisés Naím, editor in chief of Foreign Policy magazine and author of “Illicit: How Smugglers, Traffickers and Copycats Are Hijacking the Global Economy.” “I’m all for that, but I believe this decade is going to be about maximizing the quality of that trade, not quantity.”

Mr. Naím said the heparin scare is already having a “huge” impact, fueling worldwide anxiety over imported medicine and a growing demand for consumer protection.

Congressional Democrats are talking about authorizing more money so the F.D.A. can do more overseas inspections, particularly in China, where more and more drug ingredients are made. The agency is also completing a plan to permanently station employees in China for the first time.

“Just focusing on the borders of the United States does not work,” said Dr. Murray Lumpkin, a deputy commissioner at the F.D.A. “In order for us to do our job better domestically, we have to work better internationally.”

Chinese drug regulators have also begun to take small steps toward plugging some of the country’s gaping regulatory holes, particularly with the thousands of chemical companies that sell pharmaceutical ingredients without a drug license. Regulators have much to do and many obstacles to overcome in trying to adapt to changes brought on by globalization.

The way heparin is made and distributed illustrates the challenges they face. The drug’s raw material comes from mucous membranes in the intestines of slaughtered pigs. Those membranes are mixed together and cooked, a process that in China often takes place in unregulated family workshops.

It is then transported to middlemen, called consolidators, who direct the product to plants in China that manufacture heparin’s active ingredient for shipment to either another trader or the finished dose manufacturer. In the United States, the tainted ingredients ended up at Baxter International, which later had to recall the blood thinner.

Since the outbreak in the United States, Japan and several countries in Europe have recalled certain heparin products made with Chinese ingredients. In some instances, European traders buy and sell the heparin to companies in other countries, extending the supply chain even more.

Anti-counterfeiting experts say that the longer the chain, the greater the opportunity for counterfeiters to adulterate the product. In fact, F.D.A. investigators have yet to figure out where in the multistage manufacturing process the chemical that mimics heparin was added.

“Advanced technology and global manufacturing outlets have made fake drugs a big and illicit business that is literally poisoning patients,” said Alan C. Drewsen, executive director of the International Trademark Association.

And since supply chains often pass through more than one country, there is no government agency with the power to police all of it. The World Health Organization runs a program that helps track counterfeit medicine, but it has no regulatory authority.

Manufacturers also need to do a better job of testing imported ingredients, drug experts say.

For example, tests failed to detect the heparin-like contaminant because it was so similar to the real thing. And that worries Dr. Roger L. Williams, chief executive of the United States Pharmacopeia, which sets quality standards for medicine and supplements.

“What you are seeing here is the tip of the iceberg,” Dr. Williams said. “How do we know what else has gone wrong?”

He said, for example, that melamine was missed because “we have a bad test for protein.” Other tests should also be improved, he said. To help companies identify diethylene glycol, the inexpensive poison that ended up in Panamanian cold medicine and in Chinese toothpaste, USP recently came up with a better way of determining if that poison is present.

Some leading members of Congress don’t want to rely so heavily on manufacturers to protect the public, particularly afterreports said poor management and scientific inadequacies have weakened the F.D.A.

More than 500 plants in China export drug ingredients to the United States but the agency inspected only 13 of them last year.

One of the plants not inspected was the one that made the contaminated heparin ingredient. That plant, Changzhou SPL, blames someone else further upstream in the supply chain for selling tainted raw materials.

The F.D.A. is continuing to investigate.

“We can blame the Chinese for this stuff as much as we want, but the truth of the matter is we are the people who are buying,” said Joseph G. Acker, president of a chemical trade association.

And Mr. Acker points a finger at the F.D.A., adding, “I think that organization needs a total overhaul.”

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