Friday, February 1, 2013

Modern Day Teratogens


Gennarina Riso 

Teratogens are environmental factors that can negatively affect a fetus in a variety of ways. Any non-genetic cause of fetal malformation has therefore been caused by a teratogen. The phenotype of malformation observed in the fetus depends not only on the teratogenic agent, but also the dosage of exposure, exposure time, and stage of pregnancy. It is widely believed that some of the most devastating birth defects are a result of teratogen exposure very early in pregnancy, as major organ systems have not yet been developed. Some examples of environmental teratogens include radiation, infectious agents (such as chickenpox or syphilis), toxic metals (such as lead or mercury), chemical exposures, maternal conditions (i.e. obesity, hyperthyroidism, or iron deficiency), and of course ethanol, smoking, and both street drugs and prescription medications.
One of the most historically notable teratogens is thalidomide, which is an anti-emetic with antiangiogenic properties that women took to treat morning sickness in pregnancy in the 1950’s, 1960’s, and 1970’s. This resulted in many major fetal deformities, the most obvious of which is extreme limb-shortening. At the time of widespread thalidomide prescription usage in pregnant women, physicians did not understand the efficacy with which medications are able to pass through the placental barrier and affect the fetus. It was thought that if overdose in the mother did not result in her death, the fetus would be unaffected.
Figure 1. Example of children with obvious upper limb deformity secondary to maternal treatment with thalidomide during pregnancy.

 While scientists today know a lot more about the maternal-fetal placental connection and in spite of rigorous clinical testing on medications prior to dispensal, current abuse of opioid pain medications by pregnant women is not uncommon. Opioids are pain medications (such as morphine, codeine, hydrocodone, methadone, and fentanyl) that are chemically similar to opium and can bind to opioid receptors in the human body. There are four types of opioid receptors in the human body, and they are located in the brain and spinal cord, as well as peripheral sensory and autonomic nerves. The different receptors are associated with varying side effects including physical dependence, euphoria, analgesia, GI suppression, sedation, and respiratory depression. Opioid receptor localization in the amygdala speaks to its role in pain perception in humans, especially in an emotional context and also is why treatment with opioids can lead to feelings of euphoria and confusion. These receptors bind natural chemicals that help alleviate our perception of pain by blocking the release of neurotransmitters that signal pain response to nociceptors (neurons that interpret painful stimuli), while still allowing the body to have some functionality of sensory neurons and motor neurons. Opioid medications, which also bind to these receptors, result in a G-protein mediated pathway that blocks most unpleasant sensations in nociceptor neurons. While these medications certainly have their place and benefits, there are also many well-documented adverse responses to prolonged opioid exposure, as well as to overdose of opioids. Because these receptors can result in decreased neuronal activation, overdose can lead to breathing depression due to lack of communication between neurons and the diaphragm. Patients can develop both physical and psychological dependence on such medications, requiring them to increase their dosage in order to get the desired effect. After a time, even if a real pain stimulus is not present, a patient who has developed tolerance to these medications can feel very real pain if they do not have any opioids in their system to negate neuronal stimulation, which has become perceptively painful to their brains.
Figure 2. Example of effects of Mu-Opioid agonist and antagonist treatment.

           I have always found developmental biology and physiology to be fascinating (hence my choice to apply for the CIRM Program J ), so when pondering a possible blog topic for this class, I thought that I would further explore the physiology behind the disturbingly high amount of opioid prescription abuse that I have observed over the last 2 years while working in 2 local Emergency Rooms in order to gauge what the potential costs may be, not only to those patients, but to their unborn children. I was surprised to find a lack of direct cause and effect information regarding fetal opioid exposure during pregnancy. The reasons for such a lack of information are almost as interesting as the science that I did learn! Broussard, C. et al. (2011) explored correlation between congenital heart defects (CHD) and opioid treatment between 1 month before and 3 months after conception. They asked 17,449 mothers of infants with CHD and 1,200 mothers with otherwise healthy infants about their medication use before and during pregnancy. While they found that opioid use during this defined portion of pregnancy was positively correlated to several specific types of CHD, most notably hyperplastic left heart syndrome, the most serious CHD (as well as spina bifida), their data are not entirely convincing. (Interestingly, however, the CDC did post a press release in 2011 linking opiate use during pregnancy with hypoplastic left heart syndrome, as well as several other horrifying defects, in infants.)

          It is inherently difficult to obtain sound data from interviewing subjects, especially long after the event of interest. Some of the randomly selected subjects were unwilling to answer questions. Many were unsure what medications they were taking or were unsure of when they took them. In addition, there are many confounding variables such as alcohol consumption, maternal age, and location of residence. Further, even with such a large sample size, there are different types of opioids and many different variations of CHD, making it difficult to draw direct conclusions. One aspect of the study that stuck out to me was that many of the women interviewed were of lower socioeconomic status and had less education than the control group. This makes me wonder about differences in prenatal care and whether some of these women were even aware that some of their prescriptions could potentially negatively affect their baby. This study did not use data from women with known histories of heroin use, which could have had confounding effects. However, because the majority of infants born with some of these defects come from impoverished, uneducated backgrounds, there are almost infinite confounding variables that present that could also have deleterious affects on development, almost all of which are completely unrelated to medication use. In other words, some of the disparities in our society are hindering our ability to “properly” explore certain scientific questions as they relate to human populations.  
            It is common practice in the United States to treat women who have opioid dependence with methadone during pregnancy, so as to taper them safely off of opioids and avoid withdrawal that would potentially have detrimental effects on both theirs and the fetus’s health. However, methadone itself has some negative side effects for the fetus, most notably of which is “neonatal abstinence syndrome”, which is essentially fetal withdrawal from methadone. These infants may exhibit poor feeding ability, lack of coordination of reflexes, irritability, and hyperactivity of their central and autonomic nervous systems. I found it interesting that articles published by the American Society for Obstetrics and Gynecology (ACOG) reflected on the challenges of not only treating these mothers and infants, but also on the lack of compiled data on the overall health and success of these babies throughout their childhoods. Further, giving adequate prenatal care and education has proven difficult as many women who have opiate dependence (whether to prescriptions or street drugs such as heroin) tend to seek prenatal care later in pregnancy and are more likely to skip appointments.
Van Gelder, et al. (2010) also brought up a valid point that nearly half of all pregnancies in the US are unplanned, so it stands to reason that women expose their fetuses to potential teratogens before they even know that they are pregnant. Because pregnant women are usually excluded from clinical trials, it is hard to determine with absolute certainty which medications are safe for them to use during pregnancy and which are not. In fact, many studies primarily use male animal models and only use female animals when specifically examining how a particular process or agent interacts with pregnancy. Van Gelder’s research group outlines several of the most common mechanisms of teratogenic malformations in humans, several of which have been correlated to opiate use. For example, neural crest defects are fairly common birth malformations. The neural crest is a group of cells that are extremely important to early development, as they migrate and help give rise to many large structures and systems, including muscle and bone, but also, interestingly, the heart. Recall that several different types of congenial heart disease have been correlated to opiate use in pregnancy. Further, we have seen an increase in spina bifida and facial malformations (such as cleft palate) associated with medication use and which are also types of neural crest and neural tube defects.
Medications to treat cardiac arrhythmias as well as epilepsy have very well-documented birth defects secondary to oxidative stress including limb defects, neural tube defects, and cardiac defects. While opiates are not (yet) listed with these medications, many of the resulting fetal abnormalities overlap, making me wonder if opiates really do have more of a teratogenic effect than we are currently aware of.
Vascular disruption is also a common vehicle of birth defects. This can be associated both with development of vasculature of the fetus and placenta early in pregnancy, as well as disruption of already established veins and arteries later in pregnancy. One of the major effects of opiates is to cause vasoconstriction in someone who takes it, so imagine the subtle but detrimental effects that taking these could have on a developing embryo. Further, when patients go into withdrawal from opiates, major vessels can go into spasm, causing damage, preterm labor, or simply separation of the placenta from the uterine wall, even later in pregnancy.
Figure 3. Example of a patient with Spina Bifida.

Figure 4. Example of Cleft Palate.

In 2011, Tufts University published some very interesting and disheartening data regarding the growing prevalence of opiate addiction in the US. According to their studies, in 2009, a whopping 12.4 million Americans used opiates for non-medical purposes, which was significantly higher than data collected in 2002.
Figure 5.  Prevalence of opioid abuse in US from 2004-2009, published from Tufts’ study entitled “Opioid Abuse: The Managed Care Perspective”. 

This study also published some very interesting information regarding the costs of opiate abuse. They estimate that the average annual healthcare costs for someone addicted to opiates is about $20,546 – WITH insurance. Further, they estimate a total societal cost of $55.7 billion annually. While I don’t want to focus on the monetary impacts of opiate drug abuse, I do think these numbers are notable – and several years old, so the situation could (in theory) be worse today
 In conclusion, I was shocked to find a lack of articles, data, or findings that specifically point to opiates and give cause and effect information. Last week at work, I even heard one of the ER physicians tell a woman who was 37 weeks pregnant that if she wanted, she could opt for opiates, “although some people do not like to expose their infants to drugs”. I find this kind of language ambiguous and confusing. In our society, we seem to have the attitude that we should live lives free of physical pain- and under most circumstances, it is entirely appropriate to treat pain. But we really should ask ourselves, even outside of the teratogen discussion, whether  the risks of taking such powerful medications truly do outweigh the benefits. Further, despite a lack of strong data linking opiates to some of the major teratogenic effects discussed above, there is a lot of literature available that links opiate use to learning disabilities, disrupted growth patterns, and higher correlation to using drugs later in life themselves. In other words, this is a vicious cycle, and I would bet that opioids (along with many other “normal” environmental factors encountered in our lives) have significant epigenetic effects that we are unaware of at this time.


Gilbert-Barnes, E. 2010. Teratogenic Causes of Malformations. Annals of Clinical Laboratory Science. 40:99-113.

Broussard, C., S. Rasmussen, J. Reefhuis, J. Friedman, M. Jann, T. Riehle-Colarusso, and M. Honein. 2011. Maternal treatment with opioid analgesics and risk for birth defects. American Journal of Obstetrics and Gynecology. 204:414.e1-11.

Opioid Abuse, Dependence, and Addiction in Pregnancy. American College of Obstetricians and Gynecologists, Committee on Health Care for Underserved Women and the American Society for Addiction Medicine, Committee Opinion no. 524.

Birnbaum, H. and A. White. “Opioid Abuse: The Managed Care Perspective”. The Analysis Group for Tufts Healthcare Program on Opioid Risk Management. Powerpoint. 2011.

Van Gelder, M., I. Rooij, R. Miller, G. Zielhuis, L. de Jong-van den Berg, and N. Roeleveld. 2010. Teratogenic mechanisms of medical drugs. Human Reproduction Update. 16:378-394.

Sinatra, Raymond S. "Opioids and Opiate Receptors." The Essence of Analgesia and Analgesics. Cambridge: Cambridge UP, 2011. 73-80. Print.
McBride, W. G. "Thalidomide and Congenital Abnormalities." Medicine, Health, and Bioethics: Essential Primary Sources. Comp. K. L. Lerner. Detroit: Thomson/Gale, 2006. 291-93. Print.

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