A BLOG ABOUT OPIOD TREATMENT DURING PREGNANCY
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.
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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.
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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.
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Figure 4. Example of Cleft Palate.
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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”.
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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.
References:
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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