The purpose of the long posting is to give mothers-to-be some concise information about how some common illegal and legal drugs can effect their developing baby. Below is a list of some of the Top Teratogens.
Teratogens can be chemicals (man made or natural), substances, viral or environmental (bacterial, parasites, radiation) that can cause birth defects. The birth defect will only happen when the teratogen is present is concentrations higher than the bodies’ threshold level for the given teratogen. The birth defect can be obvious, such as extra body parts, or it can be behavioral changes that will not be seen to many years after birth.
The focus of this article will on the effects of drugs as teratogens. I will break the broad class of drugs into legal drugs that can be obtained over the counter or with a prescription, and illegal drugs which have to be obtained illegally. One concern with the use of illegal drugs is the inconsistency of dosage and strength of the substance in question, this fact makes it hard to determine what a “safe” dose of illegal drugs are to a developing fetus before the drug starts to act as a teratogen causing birth defects.
A classic example of a teratogen in recent history is the drug Thalidomide. Thalidomide was used to treat morning sickness and help pregnant mothers sleep in the late 1950’s to early 1960’s. One of the more disturbing birth defects was phocomelia which is failure for long bones of the body to develop correctly. As a result the child does not have the use of the effected limb.( Knobloch, J., Schmitz, I., Götz, K., Schulze-Osthoff, K., & Rüther, 2008) This type of birth defect is far less prevalent today since the use of Thalidomide in pregnant women is almost unheard of in any amount.
An important point to bring up here is how tetragons are discovered. It would be unethical for scientists to give a drug to pregnant women just to see if substance in question will cause birth defects. So most tetragons are found when a higher prevalence of an abnormality is recognized. It is at this point where a retrospective study will be carried out. Retrospective studies are used because of the ethical reasons just presented. Today most drugs are tested on animals to see the dose vs. response of new drugs coming to market for human use. Animals are used because they are good analogs for humans in most physiological pathways for drugs metabolism. Also they see the effect the drug has on pregnant subjects. I personally have carried out some of these studies on rats and the information has provided very useful information on dosage usage in humans.
The illegal drug known as cocaine, which has a scientific name of benzoyl methyl ecgonine has many harmful effects. Many studies have been done to see the effects cocaine has on the immediate user. Far less has been studied on the effects on a developing fetus. The major implications seem to be low birth weight and a higher risk for Placental abruption, which is when the placenta becomes unattached from the uterus. This can cause premature labor and is associated with a high mortality rate for the fetus. (Schempf, A., & Strobino, D. 2008,)
The mechanism of action is the same for the baby as it is for the user of cocaine. This is because the drug is carried in the blood stream which is then taken in by the umbilical cord of the baby. As a result the baby may have withdrawal symptoms when born from lack of cocaine. There is also still debate that cocaine use in pregnancy causes an increase risk of SIDS in babies, but since users of cocaine have a high probability of using other illegal and legal toxins it is hard to establish a direct cause to cocaine use. (Frank DA, Augustyn M, Zuckerman BS, 1998)
Marijuana is an illegal drug whose main compound that causes the damage to the user and fetus is Tetrahydrocannabinol. The main target for this compound is the central nervous system (brain and spinal cord). Some of the effects on the main user are increased heart rate, and decreased motor and memory. All three of those effects are controlled by the central nervous system. (O’Connell CM and Freid PA. 1984).
The effects on the developing fetus are varied and hard to come by a clear cause and effect because of the use of other controlled substances during the pregnancy. Low birth weight and low head circumference seem to be a normal trend found in babies whose mothers used marijuana during fetal development. Low birth weight seems to be tied with the high metabolism that comes as a side effect of marijuana use. The lower than normal head circumference is probably due to the fact that Tetrahydrocannabinol directly effects the central nervous system. (Fride, E., 2008, May 2)
One recurring problem in studying the effects of these illegal drugs is the dose vs. response. The fact that concentrations are unknown it is nearly impossible to come up with a “safe” amount. One solution to this problem is to use animal analogs for humans. A very interesting study was done with rats to see the effects of several types of controlled substances. This study was not looking at mutations found in the outward appearance but rather changes in the brain due to the mothers use of the controlled substance. The study was entitled “Does drug abuse beget drug abuse? Behavioral analysis of addiction liability in animal models of prenatal drug exposure.” The article does a good job in simplifying a difficult pathway analysis of how certain drugs affect the “pleasure pathways” of the brain.
. (Malanga, C., & Kosofsky, B., 2003)
The regions of the brain shown above are analogous with humans, and so their conclusions on animal finding will be applicable to humans in my opinion. All behavioral studies that model substance abuse involve observation of a sequence of behaviors relating the animal to the incentive salience of a drug or non-drug (e.g., food) reinforcer, or cues associated with that reinforcer, over time. In this study Intravenous self-administration, Intracranial self-stimulation, Conditioned place-preference and Locomotor stimulation where the methods of delivery and measurement of the drugs effect on the mind.
The results show that the offspring of the drug use animals were more apt to all four methods of reward of pleasure vs. the control group. (Malanga, C., & Kosofsky, B., 2003) So this study seams to show that while the use of some illegal drugs doesn’t cause outward mutation to the baby. But to a certain extent will cause the baby to have a higher chance of becoming a user of controlled substance by having a stronger pull to addiction than a baby that was not exposed.
We will not look at the effects of some prescription drugs and the effects on a developing fetus, followed by some over-the-counter drugs. Some women will take prescription drugs that were prescribed before pregnancy under the false since of security of “my doctor gave it to me”. I now plan to provide some examples of prescription drugs that should not be used during pregnancy.
Diazepam is better known as valium. It is used to treat a wide range of conditions such as anxiety, acute alcohol withdrawal and muscle spasms. (Drug Bank, 2008). The mechanism of action for Diazepam is an increase in hyperpolarization of the sodium gated pumps in the body; this will cause fewer brain synapses to fire or any signal to fire for that matter. (McElhatton PR. Nov-Dec 1994). Diazepam is very lipid soluble so it is able to pass into placental blood supply very easily.
The effects Diazepam has on fetal development are withdrawal symptoms at birth, due to the fact that the baby’s brain is now used to the Diazepam binding to brain receptors. Also the baby may remain in a limp state for months until the drug is completely out of the system. The baby is limp because of the hyperpolarization effect of the drug, so muscles fibers cannot fire and the baby appears limp. The child may have a problem sucking for breast milk. (McElhatton PR. Nov-Dec 1994)
Long term effects and behavioral changes are less known at this time and further research is needed. At this time the use of Diazepam is only used for life saving measures in pregnant women, and should not be used without consent from a doctor that has knowledge of your pregnancy. (Drug Bank, 2008)
Atorvastain is a drug better known as Lipitor. The use of Lipitor is very high as high cholesterol levels follow Americans increasing waist size. Lipitor is used to lower cholesterol levels by inhibiting a key enzyme that is required for making cholesterol. A study was preformed on rats to see the dose vs. response of Lipitor on mothers and the effects on the developing fetus. The results show that even in small amounts Lipitor is harmful to the fetus, by causing neurological abnormalities and low brain size. It seems to be the lethal dose for a fetus to be 100mg/kg at this level abortion was spontaneous in some of the rats. (Dostal, L., Schardein, J., & Anderson, J., 1994, December)
Cholesterol is very important in fetal development; the brain needs a lot of cholesterol for normal development. Specifically in brain cell integrity, cholesterol helps make the cells more flexible. (Lindegaard, M., Wassif, C., Vaisman, B., Amar, M., Wasmuth, E., Shamburek, R., et al. 2008,) The major source of cholesterol for the fetus is from the mother’s blood supply, so taking Lipitor will hurt the developing fetus.
Etretinate is a medication that is used to treat severe cases of psoriasis. And has a common name of Tegison. Etretinate is a known teratogen that causes. I found a case study in which a 20 week old fetus was delivered with many facial and limb abnormalities. This case shows that Doctors need to be sure to tell fertile women about the possible congenital problems that can arise from the use of Etretinate even after cessation for up to 2 years.( de Die-Smulders, C., Sturkenboom, M., Veraart, J., van Katwijk, C., Sastrowijoto, P., & van der Linden, E. 1995, October)
While most over the counter drugs pose little risk to the developing fetus, there are a couple exceptions that need more light shined upon them. And it is always a good idea when pregnant to always consult your Doctor before taking any over the counter drugs including vitamins and minerals.
Acetaminophen is an over the counter pain killer better known as Tylenol. It is used to treat headaches, toothaches, aches and pains of all sorts. It is also used to treat mild fevers. The mechanism for pain relief is that acetaminophen binds to key enzymes that bind to sodium channel gates in the pain pathways in a similar way that lidocaine works when you go to the dentist. (Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A, 2006)
The use of acetaminophen in pregnant women is still up for debate. Some studies have shown no ill effect for the baby while others have shown an increase risk for liver malformation in fetal development. One study found that developing fetuses that have a certain genetic mutation known as SULT1A3/4 have a higher change of developing liver malformations. The mutation it self does not cause the liver malformation, but rather when acetaminophen was used in early pregnancy in conjunction with the genetic mutation the elevated risk was seen. (Adjei, A., Gaedigk, A., Simon, S., Weinshilboum, R., & Leeder, J. 2008, March)
Pseudoephedrine is an over the counter drug that is primarily used as a nasal decongestant. The active ingredient is found in many over the counter drugs such as Advil cold and sinus. While the primary use of this drug is a decongestant. It is also the first treatment for Priapism, which is when a male has an erection for more than 4 hours.
The mechanism of action is that pseudoephedrine caused vasoconstriction, meaning that it will cause muscles to squeeze blood vessels more tightly. This will cause less blood flow to extremities, and sinus passageways. ( Drug Bank, 2008)
The use of pseudoephedrine is pregnancy does have some research behind it, to support not using this drug when pregnant. One study found that the use of pseudoephedrine during pregnancy was associated with in increase in fetal gastroschisis. Gastroschisis is when the abdominal wall fails to close in newborns; as a result the newborn has to have surgery to place the intestines inside of the child. The total increase in risk was not small either; the study calculated an relative risk of 4.2. Meaning that if pseudoephedrine was used during pregnancy there is a 4.2 times greater risk that the baby will be born with gastroschisis. (Gastroschisis and pseudoephedrine during pregnancy, 2004)
So what can be done
The FDA has put a lot of effort to try and inform the professional community about possible drug interactions with developing fetuses. It is very unlikely a physician will know the exact risk posed by every drug that can be given to pregnant women. So the FDA has come up with a lettering system to make things simpler for health professionals. The letter are A,B,C,D,X. the first two letters A and B are relatively safe for pregnant women to use. C and D have shown an elevated risk in either animal for human populations for developmental problems to occur. Category X is the worst, and has been shown to cause severe defects to fetal development. Category X substances should not even be prescribed to women in their fertile years. (Pregnancy and the Drug Dilemma)
(In order of appearance)
Knobloch, J., Schmitz,
Schempf, A., & Strobino, D. (2008, November). Illicit Drug Use and Adverse Birth Outcomes: Is It Drugs or Context?. Journal of Urban Health, 85(6), 858-873. Retrieved November 20, 2008, doi:10.1007/s11524-008-9315-6
Frank DA, Augustyn M, Zuckerman BS. Neonatal neurobehavioral and neuroanatomic correlates of prenatal cocaine exposure. In:
O’Connell CM and Freid PA. 1984. An investigation of prenatal cannabis exposure and minor physical anomalies in a low risk population. Neurobehav Toxicol Teratol 6:345-50. Retrieved November 20, 2008, doi:10.1128/MCB.00487-07
Fried PA, et al. 1984. Marijuana use during pregnancy
and decreased length of gestation. Am J Obstet Gynecol
150:23-27. Retrieved November 20, 2008, doi:10.1128/MCB.00198-07
Malanga, C., & Kosofsky, B. (2003, December 30). Does drug abuse beget drug abuse? Behavioral analysis of addiction liability in animal models of prenatal drug exposure. Brain Research. Developmental Brain Research, 147(1-2), 47-57. Retrieved November 8, 2008, from MEDLINE database.
Drug Bank- Showing drug card for Diazepam. Retrieved November 29, 2008 From Drug Bank, Website: http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=APRD00642.txt
McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reproduction Toxicology. 8 (6): 461–75. Retrieved November 28, 2008, doi:10.1111/j.1365-2826.2008.01670.x