ISSN
1916-694X

2010;
Volume 1 (Number 1): Pages 3-8

REVIEW ARTICLE

Studying
the safety of drugs in pregnancy: and the gold standard is…

Adrienne EINARSON

The Motherisk
Program, Hospital for Sick Children, Division of Clinical Pharmacology,
Toronto, Canada

*Corresponding author:
[email-masked]

ABSTRACT

Pregnant women are often advised not to take any medication
as it might have adverse effects on the fetus and possibly in the future on an
infant or developing child. However, for many women who are diagnosed with a
chronic illness, discontinuing their medication is not an option. Women may
also require treatment for acute illnesses, such as infections with a high
fever, which may compromise the fetus if not treated. However, studying the
safety of drugs during pregnancy is fraught with limitations, mostly because of
ethical reasons, as obviously no pregnant woman is going to volunteer to
participate in a randomized controlled trial (RCT). In the absence of RCTs,
which are the gold standard, we have to rely on observational studies, which
are usually in the form of case reports, case series, chart reviews, cohort
studies, case-control and nested case-control studies, and administrative
database studies. In this review, the various methods of studying drug use in
pregnancy are described with their accompanying strengths and weaknesses and
supported by examples from the literature to illustrate each method.  In conclusion, it appears that a combination
of methods may be used to provide evidence-based information to assist an
expecting woman, together with her health care provider, in making an informed
decision as to whether or not the use a particular drug is appropriate during pregnancy.

Key words

Drug evaluation studies; Epidemiologic research
designs; Pregnancy

RÉSUMÉ

On conseille
habituellement aux femmes enceintes de ne prendre aucun médicament dans le but
d’éviter la survenue possible d’effets indésirables chez le fœtus, le nouveau-né
et chez l’enfant au cours de son développement ultérieur. Il n’est cependant
pas indiqué d’arrêter le traitement chez beaucoup de femmes souffrant d’une
maladie chronique. Par ailleurs, l’absence de traitement chez une future mère
souffrant d’une maladie aiguë, comme une infection ou une fièvre élevée, peut
compromettre le développement de son fœtus. L’étude de la sécurité des
médicaments durant la grossesse souffre malheureusement de limitations
principalement pour des raisons étiques, à savoir l’impossibilité des femmes
enceintes à participer volontairement à des études contrôlées randomisées.
Suite à l’absence de ce ‘gold standard’ nous devons utiliser l’information
d’études observationnelles comme les reports de cas, séries de cas, revue des registres,
études de cohortes, étude cas-témoin au sein d’une cohorte, et études de bases
de données médico-administratives. Au cours de cette revue, les différentes
méthodes d’étude des médicaments durant la grossesse sont décrites avec leurs
forces et leurs faiblesses, étayées d’exemples de la littérature pour illustrer
chacune de ces méthodes. En conclusion, il apparaît que la combinaison de
différentes méthodes d’étude peut être utilisée pour procurer une information
basée sur l’évidence aux femmes enceintes et à leurs médecins pour prendre une
décision correctement informée concernant l’utilisation d’un médicament durant
la grossesse.

Mots clés

Études
d’évaluation des médicaments; Méthodes d’investigation épidémiologiques;
Grossesse

RESUMEN

Las mujeres
embarazadas generalmente reciben la recomendación de no tomar ningún
medicamento ya que podría tener efectos adversos en el feto y, más tarde, en el
niño durante su desarrollo. Sin embargo, en muchas mujeres con enfermedades
crónicas, la suspensión del medicamento no es una alternativa. Algunas mujeres
podrían requerir tratamiento para algún problema agudo, como una infección
asociada a fiebre, lo que podría comprometer al feto si la madre no recibe
tratamiento alguno. Sin embargo, el estudio de la seguridad de los medicamentos
en el embarazo está lleno de limitaciones, ya que por razones éticas ninguna
mujer va a participar voluntariamente en un estudio clínico controlado. En la
ausencia de este tipo de estudios, considerados como el estándar de oro, tenemos
que apoyarnos de estudios observacionales, que son generalmente presentados en
forma de reportes de caso, series de casos, revisiones de expedientes, estudios
de cohorte, de casos y controles, de casos y controles anidados, o de bases de
datos. En esta revisión, estos diferentes métodos de estudio de los
medicamentos en el embarazo se describen junto con sus respectivas fortalezas y
debilidades y con ejemplos de la literatura para ejemplificar cada método. En
conclusión, parece que la combinación de métodos de investigación podría usarse
para proporcionar información basada en evidencias para apoyar a las mujeres,
junto con su médico, a tomar decisiones informadas sobre cuando usar un
determinado medicamento durante el embarazo.

Palabras claves

Estudios de
evaluación de los medicamentos; Diseños de investigación epidemiológica;
Embarazo

INTRODUCTION

In the not so distant
past, it was assumed that there was a “placental barrier” that prevented any
agent from crossing the placenta and coming into contact with the fetus.
Consequently, when women became pregnant, lifestyles changed little as they
continued to smoke cigarettes, drink alcohol and take medications. However,
this practice changed dramatically following the thalidomide tragedy. This
tragedy was a warning sign that changed the “placental barrier” thinking and
set off alarms where today, almost any exposure is considered a potential
teratogen. Before discussing the current models that are used to examine the
safety of drug use in pregnancy, there are some points that need to discussed,
to allow an understanding of this field of research.

Pharmacokinetics of the
maternal–fetal unit

Almost all drugs have
been shown to cross the placenta and enter the fetal circulation in measurable
quantities.  However, it should be noted
that only the free fraction of a drug is available to cross the placenta.
Several models have been used to explain the maternal–fetal–placental unit in
terms of its pharmacokinetics. Common to the vast majority of these models
there are two main factors that contribute to pharmacokinetic changes due to
pregnancy: 1) maternal physiological changes; and 2) the effect of the
placental–fetal compartment.

These changes/factors,
which include delayed gastric emptying, decreased gastrointestinal motility,
increased volume of distribution, decreased drug binding capacity, decreased
plasma protein levels (albumin), increased hepatic metabolism due to liver
enzyme induction and increased renal clearance, can affect any or all drug
absorption, distribution, metabolism and elimination. As such, the degree and
nature of the changes in the pharmacokinetic profile of a given drug due to
pregnancy are mainly dependent on the changes in metabolic pathways to which
the agent is susceptible.

Recently, a large body
of evidence has suggested that in late pregnancy there is substantial increase
in the clearance rate of various drugs, due to increase function of different
cytochrome P450 enzymes, including nicotine (2A6), fluoxetine and citalopram
(2D6), and protease inhibitors (3A4). This could mean that women may need
larger doses to achieve therapeutic steady state concentrations. Late pregnancy
is also characterized by major changes in GFR, hepatic blood flow, protein
binding and altered drug compliance. These changes lead, in most instances, to
lower systemic exposure to drugs which are eliminated by both by the liver and
kidneys [1].

Teratogenicity

Teratogenesis is
defined as structural or functional dysgenesis of fetal organs and/or skeletal
structures. The typical manifestations include: fetal growth restriction or
death, carcinogenesis and physical malformations which may be of varying
severity, requiring surgery in extreme cases. Also included are neurobehavioral
abnormalities [2].

Fetal toxicity

Some drugs are not
considered teratogenic but rather, embryotoxic. These agents are not considered
to cause physical birth defects per se but are known to have deleterious health
effects on the fetus following long-term exposure in utero. A prime example of
a substance that is both teratogenic and embryotoxic is alcohol, which can
cause physical defects when used in early pregnancy and adverse long term
neurodevelopmental effects when used heavily throughout pregnancy [3].

STUDY OF DRUGS IN PREGNANCY

There are currently a
number of models used to study the safety of drugs in pregnancy without
performing RCTs, an unethical practice in pregnant women.

Case reports

These are considered a
signal generator as they identify a potential problem, thus allowing a formal
investigation if warranted. The major limitation of a case report is that it
cannot be a causation, unless many other cases describe the same defect with
the same exposure, as was the case in the thalidomide tragedy [4]. Of
note, in the 46 years since that landmark case report was published, there has
not been another one that that has played such a major role in discovering a
new teratogen. This is likely because since that time, pre clinical studies are
far more rigorous, with the mandatory use of three different species in animal
studies, as well as screening for signals in post marketing surveillance,
either prior to or soon after the drug was introduced to the market. An example
was in the case of isotretinoin, when even prior to its market launch, it was
known from animal studies that it could be a teratogen, and was also found to
be highly teratogenic in humans, in fact, more so than thalidomide [5].

Case series

In a case series, there
can be several cases with up to hundreds or more. The main limitation of a case
series is that there is no comparison group, so the results cannot be compared
to a group representing the population. An example of a relatively large case
series is 122 cases [6] where a
small one would only have 4 cases [7].

Prospective, comparative cohort
studies

In this model, used
frequently by teratogen information services, exposures of interests are
identified and a prospective follow up of women are enrolled in the study,
usually in the first trimester when organogenesis is occurring. Following birth
of the baby, pregnancy outcomes are obtained and compared with other women who
were not exposed to the drug in question or a teratogen and if possible a
disease matched group. The strength of this model is the personal interview
with the individual, which includes detailed history taking and whether she
actually took the drug during pregnancy. Another strength is the prospective
approach, when a woman is enrolled in the study she is in early pregnancy, so
the outcome is unknown. It also allows for a comparison between the exposed and
non- exposed group (i.e., baseline rates) of major malformations, spontaneous
abortions, etc.

The major limitation of
this model is the sample size, most often about 150 cases, which is small for
statistical purposes as it only has an 80% power to detect a fourfold increase
in major malformations. Approximately 800 cases in each group would be required
to detect a twofold increase in risk of relatively common malformations and
thousands of cases would be required to detect rare malformations. Another
major limitation is that samples are not randomly selected as women calling a
teratogen information service (the majority of instances where this model is
used) and do not necessarily reflect the general population. Women who
participate in this type of research, generally are in a higher socioeconomic
class and are generally more motivated to do the “right things” to have a
healthy baby. These studies can be conducted collaboratively with other similar
groups worldwide, as  in the case of a
study recently published on the safety of mirtazepine (n= 104) in
pregnancy, with no increase risk for major malformations, but increased risk
for spontaneous abortions [8]. On the
other hand the cases can come from a single program, as in the case of a study
(n= 176) published on ondansetron, with no reported increase for any adverse
effects [9].

Case control studies

These are retrospective
studies where the outcome is known and the group is compared to another group
who had the same outcome (in this area of study, the offspring were born with
the same birth defects). The two groups are then matched on important variables
and a search is conducted for evidence of exposure. This methodology is often
used in teratology studies because far fewer cases are required to find rare
birth defects, compared to prospective comparative cohorts. The main limitation
is the retrospective bias and the inability to not always be able to match for
confounders. A couple of important studies that have been published using this
model are a group who assessed associations between first-trimester maternal
use of SSRIs and the risk of birth defects among 9,849 infants with and 5,860
infants without birth defects participating in the Slone Epidemiology Center
Birth Defects Study: In analyses of defects previously associated with SSRI use
(involving 42 comparisons), overall use of SSRIs was not significantly
associated with an increased risks of birth defects [10]. Another
group, using data derived from a population-based case-control study that
included cases of orafacial clefts (n = 662), conotruncal heart defects (n =
207), neural tube defects (n = 265), and limb reduction defects (n = 165) found
that corticosteroid use was associated with an increased risk for isolated
cleft lip with or without cleft palate (odds ratio 4.3, 95% confidence interval
1.1-17.2) and isolated cleft palate (odds ratio 5.3, 95% confidence interval
1.1-26.5) [11].

Meta-analysis

This is a very useful
method when studying drug use in pregnancy, as most observational pregnancy
outcome studies have small sample sizes. This is a way of combining results
across different studies, enlarging the sample size, so as to make a more
definitive statement regarding safety/risk of the drug.  Usually a minimum of at least two reviewers
independently search for studies published in the literature on the drug of
interest.  A literature search is
conducted by these two individuals, using all available data bases.
Case-control and cohort studies are both accepted for analysis, as well as
abstracts presented at scientific meetings, as long as the subjects were
similar. The inclusion and exclusion process is then carried out by the two
reviewers, who independently evaluate the articles for acceptance into the
study. If necessary, a third reviewer may act as an adjudicator for any
unresolved disputes.

The reviewers then
extract the data from the included studies into 2×2 tables and the data is
analyzed. The first meta-analysis carried out using pregnancy outcome data
studies and birth defects was performed for Bendectin (doxylamine/pyridoxine),
a drug used for the treatment of nausea and vomiting of pregnancy (NVP). This
was prompted by several lawsuits against the company alleging that this drug
was a teratogen. Eventually the company withdrew it from the market due to
financial collapse as a result of defending lawsuits, none of which were ever
won by a plaintiff against the company. It was estimated that at one time 30
million women were exposed to this drug in the US and 25 epidemiologic studies
had been performed regarding its safety during pregnancy. Following the
combination of all the studies, with more than 17,000 women, there was no
increased risk for major malformations [12].

Because this is a
useful tool for evaluating conflicting evidence, many of the meta-analysis on
pregnancy outcome and the safety of drugs have been performed for this reason.
Another important meta-anlaysis was conducted that examined the use of
corticosteroids and oral clefts because there was a discrepancy between data
from a prospective cohort study and a case control study, with the prospective
study not finding an increased risk and the case-control study finding an
increased risk. Following synthesis of all the available data, the
meta-analysis did find a small increased risk [13].

Administrative data base studies

Databases are not
typically set up for pharmacoepidemiologic research as they are primarily
developed for various administrative claims payment. For this reason, important
data is often missing, especially for studies of drug use and pregnancy
outcomes. However, they often contain large numbers of individuals with
important information, so have been increasingly used in research, most
frequently to conduct post marketing surveillance. Due to the extremely large
sample sizes, there can be a potential for false positives as many statistical
tests are used and the larger the sample size, the higher the probability of
chance findings of statistically significant results with no clinical
relevance. In addition, results are usually given in Odds Ratios (OR) and the
baseline rate is rarely documented. For example, it is not very meaningful if,
after comparing the results of two groups, there is a statistically significant
OR, if the risk in both groups is below the baseline rate of what is expected
in the population. In a recent publication, researchers examined the quality of
100 abstracts from published studies that had examined the safety of various
drugs in pregnancy. In 94% of the results, when a significant OR was reported,
or even if not, baseline rates were not documented [14].

Pregnancy registries

Pregnancy registries
vary somewhat in design, which is important when examining their results. They
consist of voluntary reporting by either the women or by their health care
providers and contain varying levels of data. Some registries are driven by
pharmaceutical companies (often compelled by national or international drug
licensing agencies) and provide data on pregnancy outcome related to the
sponsor's own product. Others are organized by independent research groups and
they can be more useful as comparative data is used. The major strength of
these registries is that often they will contain prospective data, although
some do report on retrospective data, they often contain large numbers of
exposed women and can be run for several years. The limitations include the
lack of comparison groups, as well as some confounders that are not available,
such as alcohol and tobacco use, and concomitant drug use. There have been a
number of studies that have been published using these data including a large
study from GSK with more than 1,200 women exposed to bupropion in pregnancy,
who were compared to another group of women exposed to other antidepressants [15]. There
are several worldwide epilepsy registries that have been run for quite a number
of years by both industry and academia [16].

Prescription data base studies

These studies are
compiled using data from prescriptions that have been filled by the patient.
The main strength of this method is the very large sample sizes. However, there
are several limitations, the main one being that it is only known if a person
filled the prescription, not that the drug was actually taken. Another
limitation is that the collection of data is usually retrospective in nature.
One group of researchers conducted a nested case-controlled study, where they
separated a small group within a very large cohort and compared the rates of
anomalies. This group did not find an increase risk for major anomalies [17].
However, another group also published a study on the safety of antidepressants
in general where they found an increased risk for different malformations.
There was no pattern of defects, there was no separation between major and
minor malformations and there was no discussion of potential confounders [18].

National birth registries

Some countries, mostly
in Europe, operate registries where the mother and child pairs are entered
after birth and are followed up prospectively. Many studies have been published
with data from The Swedish Birth Registry [19]. The
Hungarian Case-Control Surveillance System of Congenital Abnormalities is
another group in this category who have published many pregnancy outcome
studies following exposure during pregnancy [20].

When practicing
evidence-based medicine, in the absence of randomized controlled trials (RCTs)
which is Level 1, all of these methodologies loosely fit into the category
Level II-2 [21]:
“Evidence obtained from well-designed cohort or case-control analytic studies,
preferably from more than one center or research group.”

SUMMARY

Studying the effects of
drug use in pregnancy is a complicated process with currently no ideal model
for conducting studies. Because of the ethical issues surrounding pregnancy and
conducting an RCT, it is highly unlikely that there ever will be an ideal
model. All of the models we are using have their limitations, such as small
sample size, retrospective bias, inability to know exactly if the women took
the medication in pregnancy and other missing data.  However, this does not mean that the data
collected is not valuable and useful to provide evidence-based information.
Women and pregnancy is a highly sensitive topic with health care providers,
with the media being very interested and eager to report findings, especially
if adverse effects are reported [22].
Consequently, it is of great importance when translating results, to point out
the limitations of each study and how it may affect the results. For best
evidence, a combination of these different types of observational studies will
assist women and their health-care provider in making informed decisions as to
whether or not to take a particular drug during pregnancy.

ACKNOWLEDGEMENTS

None to declare

CONFLICT OF INTERESTS/DISCLAIMERS

A E is member of the
Editorial Board of the journal.

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