NIH-funded study finds low birthweight could reduce overall effectiveness of drug treatments
Thursday, April 10, 2014
The podcast is available at http://www.nichd.nih.gov/news/releases/Documents/NICHD_Research_Dvlpmts_040314.mp3 (MP3 - 9 MB).
Addendum: Funding for the study was provided by the NIH Office of Research on Women’s Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Barrett Whitener: A new study suggests that when a child is born at a low birthweight, the child's ability to respond to certain drugs may be permanently affected. Results of a study conducted in rats suggest that, because of diminished kidney function, an individual may have difficulty eliminating drugs from their system. This poor kidney function may also result in a drug being taken up by an organ other than its intended target, such as the liver instead of the brain.
Low birthweight has two principal causes: being born prematurely, and failing to grow sufficiently while in the womb. Infants born at low birthweight are at increased risk for infant death and for such serious lifelong complications as cerebral palsy, blindness, and learning disabilities.
Today, about 8 percent of U.S. infants are born at a low birthweight—at 5 pounds, 8 ounces or less.
With me today is Dr. Ganesh Cherala, lead author of the new study. Dr. Cherala is assistant professor in the College of Pharmacy at Oregon State University, and at the Oregon Health and Science University. To simulate the effects of low birthweight, the animals' mothers were fed a low protein diet during their pregnancies.
From the National Institutes of Health, I'm Barrett Whitener. And this is Research Developments, a podcast from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NICHD.
Dr. Ganesh Cherala: Hello, Barrett.
Mr. Whitener: Doctor, what causes low birthweight, and how serious a problem is it?
Dr. Cherala: There are many causes of low birthweight. One of the causes that we focused on is maternal diet, which, if you look at a bigger picture, is a result of maternal stress. So maternal stress, whether it is induced via emotional stress or nutritional stress, will lead to a growth restriction.
So, how big of a problem this is, as you stated in your opening statement, about 8 percent of the U.S. population of newborns are low birthweight which is less than 5.5 pounds. And if you go to the global level, it's as high as 25 percent which is 1 in 4, such a high number in places like India, Pakistan, Nepal and Bangladesh, the so-called South Asia.
Mr. Whitener: And what are the negative consequences of low birthweight?
Dr. Cherala: Well, David Barker, the eminent scientist from back in the late 80s, came up with an interesting epidemiological finding based on Dutch famine studies, where he linked low birthweight to a higher risk of hypertension, hyperlipidemia (meaning high cholesterol), and diabetes. And one of the co-authors on the paper that we are discussing today, Dr. Kent Thornburg, they looked at the effects of low birth rate and later incidents of metabolic syndrome, which includes diabetes, hypertension, and high cholesterol.
Recently, we are realizing to that growing list of diseases, we should add obesity. Obesity, and the risk of becoming obese, actually has some component early on, and poor maternal nutrition would actually set the stage for the higher risk of obesity, too. So that's the range of disease we are looking at.
In addition to that, we are learning more along the lines of low IQ and higher risk of osteoporosis. So the list of diseases that are a result of poor fetal growth as well as growth immediately after birth, actually take the whole range of the first nine months of life and the first two years of post-birth. That adds up to a total of 1,000 days. So, there's a new term coined now. "The first thousand days of life" is what determines the risk for disease in later life. So, that's on the risk of disease.
Also, we are interested in understanding how the body absorbs drugs, distributes them in the body, how they are being metabolized by various organs, predominantly the liver, and lastly how it is excreted out of the body, flushed through the body.
Mr. Whitener: And why is it important to understand these processes?
Dr. Cherala: Because that would tell us how much of a drug and what kind of drug we should prescribe for a particular person.
I believe birthweight could be one of the many factors that could help us fine-tune the algorithm that will help us figure out the right drug, right dose, and right dosing regimen. In other words, it would take us a bit closer to the so-called personalized medicine.
Mr. Whitener: I mentioned earlier that your study was conducted in rats. Can you tell us more about how you conducted the study?
Dr. Cherala: We wanted to study whether low birthweight affects drug response in later life, so the first thing we needed to have was an animal model. So, how did we come up with a low birthweight rat? We took a pregnant rat and gave it 25 percent less protein. Now, that's not a drastic reduction in protein consumption, protein requirement, so we gave a moderate protein restriction throughout gestation and lactation, and because of that 25 percent moderate restriction, we ended up with a low birthweight rat and the birthweight reduction was roughly 18 to 20 percent. So, it's a significant decrease.
Then, we let the offspring feed on a normal diet, and when they became adults, we looked at day 150, which in rat age is the equivalent of human middle age, and we gave them a drug. But before we gave them the drug, we wanted to get some baseline response of the drug. So, the day before we gave them furosemide, the diuretic, we actually got the baseline urine output, where we found no difference between a low birthweight rat and a normal birthweight rat. But the day after, when we gave them a dose that's the equivalent of 80 milligrams, which is the highest prescribed dose of furosemide in humans, we found a significant drop in urine output between the low birthweight group and the normal birthweight group. Is it because less of the drug is making its way into the kidney? We found that the answer was yes.
And the follow-up question to that is, why is there a decreased availability of the drug to the kidney? We found that it is because of the way drugs are being presented to the kidney. Kidneys in low birthweight subjects are roughly about 70 percent of normal birthweight subjects.
So, to begin with, low birthweight subjects have less nephron filtering units, and as a result, less of the drug made its way into the kidney, where it's supposed to act.
Mr. Whitener: Dr. Cherala, what are the implications of your research for human patients who are born at a low birthweight?
Dr. Cherala: Based on what we have seen in an animal model, I would believe that for low birthweight subjects, when they become adults, drug dosage needs to be adjusted. Based on what we have seen, I believe it would be more towards the increasing of dosage than decreasing.
So, to get the same effect as a normal birthweight subject, a low birthweight subject probably needs to be started at a higher dose, and/or maybe more frequently. So, I think that's probably a very general statement of what kind of changes we need to make in doses for low birthweight subjects.
Mr. Whitener: So for instance, a painkiller might end up being metabolized in the liver instead of making its way to the brain, where it's supposed to function, and someone born at a low birthweight might need more of that same drug to have the same effect?
Dr. Cherala: I would say so, but let's also look at the other side of it. Since the liver is metabolizing probably at a higher rate than needed, those metabolites at times could be eliciting some side effects. So I'd probably be more tempted to say increase the dose. I guess we need to look on a drug-by-drug basis to see that the increase in metabolism isn't also resulting in some unwanted side effects. If those side effects outweigh the benefit, then probably that needs to be taken into consideration too.
Mr. Whitener: I've been speaking with Dr. Ganesh Cherala, assistant professor in the College of Pharmacy at Oregon State University, and at the Oregon Health and Science University. Doctor, thanks very much for joining us today to discuss your research.
Dr. Cherala: Thank you!
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov/.