Introduction
Pregnant women are poorly represented in clinical drug trials. Around
80% of pregnant women receive medication during pregnancy, most of
which are used in an off-label manner and lack information on potential
teratogenicity [1]. In fact, from 2000 to 2010, the U.S. Food and
Drug Administration (FDA) approved 172 new drugs, 98% of which lack
data on teratogenicity and 73% had no data on safety for use during
pregnancy [2]. Many women with pre-existing conditions such as
asthma, chronic hypertension, and diabetes might be taking medication
prior to conception. In addition, the physiologic changes in pregnancy
can exacerbate existing medical conditions or induce new medical
conditions that require treatment. This highlights the importance of the
availability of safety data on drugs prescribed during pregnancy. To
complicate matters further, the doses of drugs used during pregnancy are
extrapolated from clinical drug investigations performed in men and
non-pregnant women and/or from animal models, raising questions about
the pharmacokinetics and pharmacodynamics of these drugs during the
different stages of pregnancy [3].
One of the landmark events in obstetric pharmacology was the thalidomide
disaster that occurred in the 1960s. This drug, used for morning
sickness in pregnant women, was found to be teratogenic, causing
devastating skeletal deformities in prenatally exposed fetuses [4].
Another drug, diethylstilbestrol, a synthetic estrogen, was initially
prescribed to women with threatened pregnancy loss and then was marketed
as routine for prophylaxis of possible pregnancy loss for all
pregnancies during the 1950s [5]. Twenty years later after continued
and extensive use, a small study showed an increased risk of clear cell
carcinoma of the vagina in females born to diethylstilbestrol-exposed
pregnant women among other comorbidities before regulatory action was
taken to curtail its use [6]. Historically, after the thalidomide
and diethylstilbestrol negative outcomes, the US FDA has excluded
pregnant women from phase 1 and phase 2 trials in 1977 over concerns for
the safety of administering drugs in pregnancy, after which the
pharmaceutical companies extended this exclusion into phase 3 and phase
4 [7]. These examples among many others underscore the importance of
risk and benefit assessment of medication use during pregnancy. However,
the current evidence to support this assessment is sparse. In this
review, we aim to highlight a) the need for inclusion of pregnant women
in clinical trials, b) what legislative actions were taken to curtail
obstacles for their inclusion, and c) possible solutions for clinical
pharmacology researchers.