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.