Transcript of radio interview on Terbutaline and autism, August , 2005
The following is a transcript from AutismOne Radio Interview with Lawrence P. Kaplan, PhD on terbutaline and autism that took place in August of 2005. Please read the Disclaimer link at the bottom of the page. As stated in the General Disclaimer - No Medical Advice: THE CONTENT ON THE USAAA WEB SITE, NEWSLETTERS OR OTHER ELECTRONIC INFORMATION SENT VIA EMAIL IS PRESENTED IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY. THE CONTENT IS NOT INTENDED IN ANY WAY TO BE A SUBSTITUTE FOR PROFESSIONAL MEDICAL ADVICE. ALWAYS SEEK THE ADVICE OF YOUR PHYSICIAN OR OTHER QUALIFIED HEALTH PROVIDER WITH ANY QUESTIONS YOU MAY HAVE REGARDING A MEDICAL CONDITION.
Interview conducted by Teri Small (now Teri Arranga), August 23, 2005 on AutismOne radio with Lawrence P. Kaplan, PhD. Please note current updates to this interview at the bottom of the page. Please note the FDA Drug Safety Communication issued on February 17, 2011, "FDA Drug Safety Communication: New warnings against use of terbutaline to treat preterm labor," at the following link: http://www.fda.gov/Drugs/DrugSafety/ucm243539.htm
TS: You mentioned a while back when we first started talking that Gail was given Terbutaline when she was pregnant with your twins. What is Terbutaline?
LK: Terbutaline is an asthma drug. Terbutaline also relaxes some other types of smooth muscles, such as the muscles of the uterus; however, other types of muscle may be stimulated to contract rather than relax. Terbutaline was first approved by the FDA in 1974. It is not approved by the FDA for use as a pre-term labor drug; it is "used off-label (an unapproved use) for acute obstetric uses, including treating preterm labor and treating uterine hyperstimulation". 
TS: Why is Terbutaline prescribed for preterm labor? Is it prescribed at the same or higher dosages than those advised for asthma?
LK: Terbutaline is prescribed to reduce uterine contractions and may inhibit labor. It is called Tocolytic therapy (anti-contractions medication) which simply means the delaying or inhibition of labor during the birth process.
Terbutaline is prescribed at higher doses than those advised for asthma. The side effects are more severe at higher dosages. A woman is taking 33% more than the recommended maximum dose for asthmatics.
I don’t have the actual dosage that was given to my wife Gail, but she was on Tocolytic therapy for over 30 days. Approximately 3 weeks before the boys were born she was exposed to another Tocolytic agent, even more potent than Terbutaline, called Magnesium Sulfate.
TS: What are the side effects of Terbutaline to the mom and the newborn?
LK: This is an interesting question. Do many women know what the side effects are to both her and the fetus well in advance of the potential administration of Terbutaline? Probably not. This brings up the discussion of obstetrical counseling and informed consent. Obstetrical counseling should be given at the beginning of pregnancy in case of eventual preterm situation so that women can research in advance of a critical point, that being early contractions with potential administration of drugs. At a critical point, the woman must make a spot decision, and she is going into it pre-conditioned that the FDA, the drug manufacturer, the hospital and the health care practitioner team protects her fetus or multiples.
Informed consent is consent by a patient to a surgical or medical procedure after achieving an understanding of the relevant medical facts and the risks involved. Have you, the patient discussed all the potential risks that could occur during your pregnancy? A typical consent to treatment would be as follows:
I (and your name) hereby voluntarily consent to medical care at OB/GYN Inc., encompassing routine diagnostic procedures, examination and medical treatment including, but not limited to, routine laboratory work (such as blood, urine and other studies), heart tracing and administration of medications prescribed by the physician.
I further consent to the performance of those diagnostic procedures, examinations and rendering of medical treatment by the medical staff and their assistants, including nurse practitioners, physicians' assistants, medical assistants, or their designees as is necessary in the medical staff's judgment. It all boils down to trust, but make sure that you fully understand all the risks and procedures that may be involved.
Our doctor stated that since Gail’s contractions had increased substantially, and she may deliver prematurely 3 weeks before the twins gestational period, that they were going to administer Magnesium Sulfate to hopefully prevent premature labor. I was not informed until she was taken into a separate room for the administration of the drug. I know that my wife was terrified in delivering almost a month early. We trusted our practitioners in making the correct decision, as my wife would not have been able to fully understand the implications of the effects of the drug both to her and the twins. As she said to me later, when they administered the drug to her, she said it was the worst experience she had ever encountered. You can imagine the impact it had on the fetuses. Now here are some of the side effects. First for Terbutaline:
- Maternal side effects: Cardiac or cardiopulmonary arrhythmia, tachycardia, jitteriness, and tremors. (I remember well when Gail had multiple tremors and she was very jittery every time she received bolus doses of Terbutaline). Bolus – pump. A nurse tried to explain to Gail a procedure on how to self administer the Terbutaline doses. Gail was shaking the entire time due to previous accumulations of Terbutaline doses. She could just not think straight under these circumstances. Terbutaline was certainly affecting her mentally, too.
- Fetal and neonatal side effects: Fetal tachycardia (which was experienced with our twins and the increase in heart rate was very significant for Nathan – his heart rate would increase to over 180 after each dose of Terbutaline – I would just shutter every time Gail received an automatic dose of Terbutaline), hyperglycemia, myocardial ischemia, and cardiac arrhythmia to name a few.
I also want to mention the fetal and neonatal side effects of Magnesium Sulfate Therapy:
- Motor depression (This is associated with Asperger Syndrome). Is there a connection here with ASD and Magnesium Sulfate?
- Decreased muscle tone and drowsiness
- Respiratory depression and again just to name a few.
TS: Is Terbutaline approved by the FDA for preterm labor?
LK: NO. “… the U.S. Food and Drug Administration has not approved its use to prevent premature labor.” Dr. Stuart L. Nightingale, Associate Commissioner for Health Affairs at the FDA issued a statement on November 13, 1997 that said that the FDA would like to call to your attention concerns about subcutaneous administration, via infusion pump, of terbutaline sulfate for the treatment and prevention of preterm labor. The use of terbutaline sulfate to treat preterm labor is an unapproved or "off-label" use. No benefit from prolonged treatment has been documented. In addition, the safety of long-term subcutaneous administration of terbutaline sulfate, especially on an outpatient basis, has not been adequately addressed... The impact of long-term use on maternal glucose metabolism and the risks of prolonged exposure of the fetus are largely unknown." 
TS: Has the FDA warned doctors?
LK: The FDA has warned doctors that the treatment is potentially dangerous and might not be effective.
In 1997, however, the FDA warned doctors that the terbutaline pump has not been demonstrated to be effective and is potentially dangerous.
TS: Have all doctors listened?
LK: In 2002, 63 per cent of the more than 392,000 prescriptions for terbutaline pills were for pregnant women. I don’t think they have listened.
TS: Is there conclusive evidence that Terbutaline is effective for preterm labor?
LK: The American College of Obstetrics and Gynecology (ACOG) stated that to date, no studies have convincingly demonstrated an improvement in survival or any index of long-term neonatal outcome with the use of tocolytic therapy.
TS: Have any doctors commented on the use of Terbutaline?
LK: “Dr. John Thorp Jr., at the University of North Carolina found that the drugs were not effective in prolonging pregnancy for a long term and can cause a range of harms, including heart-rhythm disorders and heart failure in mothers.
According to Dr. Washington Hill in Florida, the best use of terbutaline is a series of three injections to calm contractions for about 48 hours of so, enough time to administer steroids to help the babies’ underdeveloped lungs. But he says that doctors still send women home with long-term prescriptions for terbutaline pills.
TS: Tell us about the Johns Hopkins study of fraternal twin pairs.
LK: Andrew Zimmerman, a pediatric neurologist and Susan Connors, a physician and mother of an autistic child along with researchers from Johns Hopkins teamed up to study the connection between terbutaline and autism. They compared fraternal twins born to women who had taken terbutaline for at least two weeks during their pregnancies to the twin children of women who had not taken the drug. They then calculated the rate of concordance for each group of twins, with concordance meaning that both siblings in a pair of twins had autism. 
TS: Was there a difference in whether one or two of the twins had autism depending upon how long the mother took Terbutaline?
LK: Yes. The study revealed that women who had taken terbutaline were significantly more likely to have both twins who developed autism. In ten of the pairs both twins were concordant for autism—that is, both twins exhibited the disorder—while in eight “discordant” pairs, only one twin was autistic. (This was the case with us, where only one twin, the smaller, was diagnosed with autism). Half of the twin pairs concordant for autism had been exposed to terbutaline for two weeks or more, while seven of the eight discordant pairs had not been exposed to the drug for an extended period. (Again, this was not the case with us where Gail and the twins were exposed for well over a two week period). Remember, this study was a small sample. We should look in the weight discordance of the twins. With our boys there was a 25-30% weight discordance.
TS: Was it also suggested that a gene caused a heightened risk to Terbutaline?
LK: The researchers have conducted further studies suggesting that a variant of the B2AR gene increases the risk. “The researchers [at Johns Hopkins] hypothesize that various environmental factors – chemicals, drugs, stress – can overstimulate B2AR gene.
Connors and her colleagues hypothesize that the drug terbutaline leads to autism by interfering with B2AR, cell-membrane proteins that play a major role in brain development. Connors says that animal studies of terbutaline have shown that it overstimulates beta 2 receptors. As a result, she explains, the receptors produce excess cell-to-cell signals, confusing the development process. Connors and her colleagues suggest that this effect alters nervous system growth, putting some children at risk of developing autism when exposed to various environmental insults.
TS: Can the neurological effects and the outward behavioral expression of damage from Terbutaline be the same as that seen in autism?
According to Childbirth solutions, the neurological effects, as well as the outward behavioral expression, can be identical to autism. The total picture becomes one of disorganization in the central nervous system and concurrent physiological and behavioral dysfunction. These neurological findings are similar to those found in the brains of children with autism.
TS: Tell us about the research of Melissa Rhodes of Duke University.
LK: Melissa Rhodes and colleagues recently administered terbutaline to neonatal rats at a developmental stage similar to that of late fetal development in humans.  The researchers report that the drug “elicited neurochemical changes indicative of neuronal injury and reactive gliosis (which is a process leading to scars in the central nervous system),” and that further evaluation revealed structural abnormalities in the cerebellum and hippocampus. Particularly notable was a reduced number of Purkinje cells and thinning of the granular and molecular layers in the cerebellum, a region strongly implicated in autism.
Rhodes said that these effects point to a causal relationship between fetal terbutaline exposure and the higher incidence of cognitive and neuropsychiatric disorders reported for the offspring of women receiving terbutaline therapy for preterm labor.
In related research, Rhodes found that rats exposed to terbutaline during the neonatal period experienced brain changes that made them abnormally susceptible later in life to the harmful effects of neurotoxins. Dr. Theodore Slotkin, a part of the research team, said that he could see the biochemical evidence of the damage from the combination of terbutaline and the neurotoxin CPF early on. The functional and structural changes emerged or were evidenced in adolescence or adulthood. This is quite alarming news to me since our son is in early stages of adolescence. Is this something that all of a sudden just appears?
Also, the research team from Duke found that rats exposed to the pre-term labor drug terbutaline caused damage to brain regions known to play a role in learning and memory. The result might therefore help to explain earlier suggestions that children whose mothers are administered terbutaline suffer cognitive deficits.
As Dr. Slotkin explains that it is increasingly clear that environmental toxicants target specific human subpopulations. This study suggests that early drug or chemical exposures might underlie some of these differences in susceptibility. He says that we need to start looking for such vulnerable groups and considering them when making decisions about legislation. It is not adequate to set the allowable concentrations for certain chemicals at levels that might be unsafe for large segments of the population.
TS: Why do you think only Nathan was affected?
LK: An identical twin of a child with autism has a 75 to 90 percent chance of having autism as well. A fraternal twin of a child with autism has a 5 to 10 percent chance of having autism. So statistically, autism is infrequent in fraternal twins compared to identical twins.
Nathan was 25% discordant in fetal weight compared to his twin brother. At birth he weighed 4 pounds 5 ounces to Daniel’s 5 pounds 10 ounces. Thirteen years later the weight difference between the boys is 41%.
Why one and not the other? I believe that based on the information from the Dept. of Health and Human Services of fraternal twins both developing a developmental disorder is uncommon that it would partially explain why they both did not develop neurological disorders. Dr. Slotkin pointed out that environmental toxicants target specific human subpopulations.
It seems that Nathan’s twin, Daniel, was receiving additional nutrients during fetal development as evidenced by post placenta evaluation. It is evident to me that the primary cause of his pervasive developmental disorders and intestinal complications is "iatrogenic" disease attributed to Magnesium Sulfate, Terbutaline, mercurial and aluminum poisoning as well as other environmental insults including viral infection.
Please note current updates to this interview:
Last paragraph updated February 19, 2011.
1. February 17, 2011 - Terbutaline: Label Change - Warnings Against Use for Treatment of Preterm Labor
2. Methodology, management of pre-term labor- http://www.ncbi.nlm.nih.gov/books/NBK33241
3. In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes.
4. Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex
Viral infection - Association of autism with polyomavirus infection in postmortem brains