Pregnant Women in Clinical Trials
Pregnant Women in Clinical Trials
No Medication without Clinical Trial Representation: The Ethics of Clinical Research Guidelines that Exclude Pregnant Women
By Megan Altier
Historically, FDA and pharmaceutical regulations have excluded pregnant women from clinical trials for numerous reasons, most importantly being the risks to the mother and fetus. Because of this, these women are left subject to harm in relation to safety, autonomy, risk, beneficence, and nonmaleficence. This paper will discuss these values in addition to the COVID-19 vaccine, how fetal and maternal life are valued, along with background about bioethical and topical landmark occurrences such as the Thalidomide Tragedy and the structure of clinical trials. It will conclude with a discussion of important factors acknowledged in the paper and potential next steps and ideas for the future of pregnant women in clinical trials.
Table of Contents
- Operation of Clinical Trials
- Key Stakeholders
- COVID-19 Vaccine Trials and Pregnancy
- Ethical Question
- Fetal vs. Maternal Health-Which Should Be Valued More?
- Evaluating Risk vs. Benefit in Clinical Trials
Imagine yourself in this scenario: You are a pregnant woman who wants to receive the COVID-19 vaccine any time before August 2021. Pregnant women have been excluded from the clinical trials since the start of the mRNA COVID-19 vaccine development process, so you have no real data as to how the vaccine will affect someone in a similar condition to you. You decide to not receive the vaccine, and from the time it takes until August 2021 is reached, when the Centers for Disease Control and Prevention (CDC) releases information confirming the vaccine’s safety for pregnant women despite its initial release in December 2020, you or your developing fetus suffers devastating consequences from contracting COVID-19, an infection that might have been prevented if pregnant women had been included in the clinical trials to begin with.
To put this scenario into perspective, the information released by the CDC was in support of vaccination for pregnant women based on the data collected by the CDC’s pre-existing safety systems and its “V-Safe Pregnancy Registry”, which uses technology such as text messaging to check in on the health of pregnant women after their COVID-19 vaccinations. The organization claimed that there was not “an increased risk of miscarriage among nearly 2,500 pregnant women” injected with the vaccine, and this, combined with the high COVID infection rate of pregnant women and the pregnancy complications the disease can cause, convinced the CDC that it was safer for pregnant women to be vaccinated than not. Nevertheless, pregnant women are still hesitant to receive the vaccine for numerous reasons, many pertaining to its potentially harmful effects on both the fetus and mother.
The Food and Drug Administration (FDA) states that “in general, pregnant women are excluded from drug development clinical trials” due to Agency concerns about the potential risks for the fetus and the mother. There are limited exceptions to this policy when, in the vague terms of the FDA, “it may be scientifically and ethically appropriate to include pregnant women in a clinical trial.” The FDA’s concerns regarding the risks involved with including or excluding pregnant women from clinical trials raise a certain ethical question: is it ethical to exclude pregnant women from clinical trials of medications that are likely to be prescribed to or for pregnant women?
This paper will primarily examine this question and focus on clinical trials for the COVID-19 vaccine, how fetal and maternal life are valued, and the ethical values and considerations of safety, autonomy, risk, beneficence, and nonmaleficence. It will also limit the scope of the clinical trials mentioned to general trials as opposed to trials specifically created for pregnant women.
In order to fully understand the history of the exclusion of pregnant women in clinical trials, a discussion and recap of relevant events and regulations is necessary.
Nuremberg Trials and Nuremberg Code
To begin, after the conclusion of World War II, the Nuremberg Trials were a series of thirteen trials in Nuremberg, Germany (HISTORY) proposed and led by the Allied forces as an initiative to punish Nazi and Axis leaders for their monstrous war crimes against “Jews, Roma and Sinti people (sometimes referred to as ‘Gypsies’)… black people… Slavic people… disabled, either mentally or physically…gay people…[p]olitical opponents, primarily communists, trade unionists and social democrats…and Jehovah’s Witnesses” (Holocaust Memorial Day Trust). On October 18, 1945, the trials began, and twenty-four Nazi government officials were indicted during the Trial of the Major War Criminals before the International Military Tribunal (HISTORY) and charged with “crimes against peace, war crimes, and crimes against humanity” (National WWII Museum). Crimes against humanity can be defined as “murder, extermination, enslavement, deportation…or persecutions on political, racial, or religious grounds” (National WWII Museum), and on October 1, 1946, an additional nineteen former Nazi officials were convicted and three were acquitted. Twelve of the nineteen who were convicted were sentenced to death, three defendants were sentenced to life imprisonment, and four were sentenced to prison (National WWII Museum). Countless additional interrogations and trials occurred as well, and a result of these trials was the Nuremberg Code, “the most important document in the history of the ethics of medical research,” according to the New England Journal of Medicine. It set standards for conducting research on human subjects after the Nuremberg Trials examined the experiments conducted by Nazi doctors during the Holocaust. The Nuremberg Code is as follows:
1. The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probabl[e] cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject (United States Holocaust Memorial Museum).
Image from Wikimedia Commons
Thalidomide caused the “…shortening and absence of limbs, malformation of hands and digits, damage to ears and eyes, sensory impairment, facial disfigurement/palsy and damage to the brain, internal organs and skeletal structure.”– Thalidomide Trust
Contergan, Distaval, Tensival, Valgraine, and Asmaval; no matter the name, thalidomide’s reputation precedes it. The drug was developed in Germany in 1954 by Chemie Grunenthal shortly after the creation of the Nuremberg Code and was marketed to pregnant women to provide morning-sickness relief, even though it had not been tested on pregnant women or animals, thus making it impossible for any data to be collected regarding how pregnant consumers might react to the product or how it might affect their offspring (Thalidomide Trust). Additionally, there was no placebo group tested, an indication of the length of the trials, or a measure of the thalidomide in the blood or tissue of the participants taking it. No studies were double-blind either (Understanding Animal Research), meaning there was never a case where neither the researcher nor the participant knew which treatment the participant was receiving until the trial was complete, which is important in removing bias from the trial and its results (National Institutes of Health). Throughout the 1950s and 1960s, countless soon-to-be mothers around the world ingested the drug, with the exception of the United States as FDA reviewer Frances Kelsey refused to approve of it due to the lack of data supporting its safety in pregnant women (USA.gov). She ended up protecting many American mothers, but there were still some who were able to access the drug through international connections or traveling abroad. Additionally, the mothers outside of the U.S. who did not have the protection of the U.S. FDA took thalidomide and found that it caused irreversible and extremely consequential birth defects in many children, such as the “shortening and absence of limbs, malformation of hands and digits, damage to ears and eyes, sensory impairment, facial disfigurement/palsy and damage to the brain, internal organs and skeletal structure” (Thalidomide Trust). Approximately 10,000 babies were affected by thalidomide as a result of the ignored safety of the pregnant women and the fetuses in clinical research, causing an incomprehensible amount of harm and pain to both parties. The thalidomide tragedy caused such an amount of devastation worldwide that in 1977 the FDA excluded “all women of childbearing potential” from clinical trials in response to it. The reasoning behind the exclusion was to prevent new drugs from following in thalidomide’s footsteps and causing harm to fetuses. This was later repealed in 1993 due to its paternalistic nature and how it denied “young women the opportunity available to men and older women to participate in early drug development research” (FDA). Even though no proper clinical trials were conducted on thalidomide in the United States or elsewhere, the severe and widespread birth defects caused by this drug have had a lasting and significant impact on how clinical trials operate and whether pregnant women or fetuses are included in clinical trials research.
National Research Act of 1974
Occurring at the same time as the Thalidomide Tragedy was the U.S. Public Health Service Study of Untreated Syphilis at Tuskegee, Alabama, a non-interventional, or observational, study of the effects of syphilis conducted from 1932 to 1972, that violated the ethical principles of respect for autonomy, nonmaleficence, and justice, along with informed consent (CDC). Minimal healthcare above that at the basic level was provided to the men throughout the study, even when they died or suffered health consequences (CDC). However, this access to care was an incentive for participation in the study since many participants had little access to or ability to afford medical care at that time. In 1929, penicillin, a form of antibiotic, was developed and available for purchase as an over-the-counter (OTC) medication in the U.S. in 1945, which quickly became the new standard of care for syphilis treatment (Science Museum). Despite this development, the participants involved in the study were actively prevented from being given penicillin, which would effectively treat syphilis. In fact, the researchers were “able to gain the cooperation of the Macon County draft board [the county in which Tuskegee resides] to decline conscription of those enrolled in the study in order to not disrupt the study”, as penicillin was “mass produced during World War II for the troops” (New World Encyclopedia). If these men were drafted, they would leave the study and would be administered penicillin, thus altering the results of the experiment. Because of this military exemption (and therefore exemption from penicillin use), the basic medical treatment the participants received throughout the study was not up-to-date. This lack of adaptation to new treatment standards makes the study even more unethical, and PHS venereal disease investigator Peter Buxtun decided to publish these occurrences of the study in the media, working with Jean Heller of the Associated Press (Associated Press News) after the U.S. Public Health Service itself refused to or failed to take any action. This caused the National Research Act of 1974 to be created and signed into law. To summarize, this Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (The National Commission), which indicated certain bioethical standards to be required when conducting research of any kind, such as necessitating voluntary informed consent from each participant in any study or clinical trial before starting them (National Institutes of Health). The National Commission published a report entitled “The Belmont Report” in 1978 that “identifies basic ethical principles and guidelines that address ethical issues arising from the conduct of research with human subjects” (Office for Human Research Protections). It brings up the key bioethical principles of Respect for Persons, Beneficence, and Justice, which are crucial aspects of evaluating clinical research and bioethical situations, and the National Institutes of Health (NIH) indicates its main purpose as protecting “subjects and participants in clinical trials or research studies,” which by definition includes pregnant women.
Congress asked the Commission in 1974 to make recommendations for the inclusion of pregnant women in clinical trials, and having been influenced by the Thalidomide Tragedy and the 1973 Roe v. Wade decision, it came up with 45 Code of Federal Regulations (C.F.R.) which was later amended in 2001.
This regulation mainly addresses the organization and operation of the FDA and clinical research investigations but also that pregnant women are permitted to participate in clinical trials if the “purpose of the activity is to meet the health needs of the mother” or fetus. The terminology used in this regulation is very vague, which leaves a large amount of room for interpretation when applied to real-life clinical research, for example, what qualifies as “health needs?” Additionally, it states that research can only be done if “the risk to the fetus is minimal,” which brings up the need for a definition of risk to the fetus and what can reduce the amount of risk the most. This point is supported by the statement that “[f]urther clarification of the regulations and explications of certain wording is needed in order to facilitate practical implementation. For example, despite the fact that several ethicists have tried to define minimal risk, the wording remains ambiguous and there is no consensus on how to weigh risks and potential benefits” (Clinical Research Involving Pregnant Women 73). Part of the reason for this lack of determination of what qualifies as “minimal risk” for a fetus is that many standard qualifications cannot apply to it, such as the “study poses no more risk than expected in daily life” (NIH). In this case, because there is no “daily life” for the fetus, how can its amount of risk in clinical trials be determined? This is where researchers and pharmaceutical companies encounter problems; because they cannot determine the appropriate amount of risk to be taken, they must evaluate the amount of harm done if they were to include or exclude the pregnant woman carrying the fetus from their clinical trial(s).
There have been numerous federal documents written after the National Research Act of 1974 that pertain more specifically to setting guidelines for including and excluding pregnant women and their fetuses in research, and the next section of this paper will identify and describe several of these documents.
FDA “Pregnancy and Lactation Labeling Final Rule” (2014)
This rule requires the information presented on drug labels to “assist health care providers in assessing benefit versus risk and in subsequent counseling of pregnant women and nursing mothers who need to take medication, thus allowing them to make informed and educated decisions for themselves and their children” (FDA).
FDA “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials Guidance for Industry” (2018)
These revised FDA guidelines pertaining to pregnant women in clinical trials provide for more of their inclusion in them. Certain changes to the former guidelines have been made in terms of how the trials are conducted, and the FDA describes a few of these changes:
“Because of the complex ethical issues involved in designing clinical trials that include pregnant women, sponsors should consider including an ethicist in planning their drug development programs. Moreover, sponsors should consider meeting with the appropriate FDA review division early in the development phase to discuss when and how to include pregnant women in the drug development plan. These discussions should involve FDA experts in bioethics and maternal health.”
Additionally, the FDA’s current reasons for the inclusion of pregnant women in clinical trials are:
– “Women need safe and effective treatment during pregnancy
– Failure to establish the dose/dosing regimen, safety, and efficacy of treatments during pregnancy may compromise the health of women and their fetuses
– In some settings, enrollment of pregnant women in clinical trials may offer the possibility of direct benefit to the woman and/or fetus that is unavailable outside the research setting
– Development of accessible treatment options for the pregnant population is a significant public health issue” (FDA).
This brief history of pregnant women in clinical trials provides a sense of the present-day legal and medical guidelines regarding the topic and examines the formation of standards of ethical and clinical research along with how they should be applied specifically to pregnant women. Keeping this information in mind, I will now discuss the operation and purpose of clinical trials.
Operation of Clinical Trials
The Merriam-Webster Dictionary defines the word “clinical” as “involving direct observation of the patient” and “trial” as “made or done as a test or experiment,” which implies that a “clinical trial” is a test or experiment involving direct observation of the patient. A common form of clinical trial is a Randomized Controlled Trial, or RCT, which is “a study in which randomization,” a process using chance, “is used to assign patients to treatments. The purpose of the randomized controlled trial is to: (1) to guard against any use of judgment or systematic arrangements leading to one treatment getting preferential assignment; i.e., to avoid bias; (2) to provide a basis for the standard methods of statistical analysis such as significance tests”, according to the FDA. A clinical trial aims to “control”, limit, or eliminate differences between people in the control and the test groups, even differences that might arise through the behavior, interaction, or conversation of a researcher with a patient that the researcher knows is or is not receiving the experimental treatment. Each participant is given a number which is sent to a computer program, and this program is designed to give the active drug or the placebo to a given participant. These clinical trials are also double-blind, meaning the participants, researchers, and sponsors involved in the clinical trials do not know whether the participant received the active drug or placebo (NIH). This is done to reduce bias and other influences in the study, as placebo participants are less likely to report symptoms if they know they have the placebo. Another form of clinical trial is an open-label trial in which it is known whether the participant receives the active drug or the placebo (NIH).
A “clinical trial” is a test or experiment involving direct observation of the patient.
The format in which clinical trials operate begins with the development of the chemical structure of the drug. In the case of a new molecular entity, discovering the new molecular entity comes first. However, some RCTs are conducted on existing compounds or drugs to research potential new uses of the product. Once the chemical structure has been created, animal studies (often mouse and sometimes canine studies) occur in non-clinical research to examine its effects on fertility and reproductive health, teratogenicity, or “the ability to cause defects in a developing fetus” (Science Direct), and the birthing process. After non-clinical research are the phases of clinical trials, starting with Phase 1, which is the first time the active drug is given to a human being. It is usually tested on a small number of healthy participants between 18-40 years old, is administered multiple times a day, and the pharmacodynamics and pharmacokinetics are observed, or in other words, the effects of the drug on the body and the effects of the body on the drug. These are dose-ranging studies designed to try to identify potentially optimal doses. In a Phase 1 drug trial in the United Kingdom on March 13, 2006, “eight men took part in a ‘first in man’ phase 1 clinical trial of TGN1412, a humanized agonistic anti-CD28 monoclonal antibody being developed by TeGenero to treat various diseases in which T cells are involved, such as chronic inflammatory disorders or haematological malignancies” (NIH). The results of this trial were multiorgan failure for all eight participants, head swelling, infection, amputation of limbs, and other deformities and pain-causing ailments, all of which caused immense harm. Because of these devastating effects, “the final report of the Expert Scientific Group on Phase One Clinical Trials was published with 22 recommendations to increase the safety of future clinical trials involving first human exposure to agents with potential high risk” (NIH), along with altering the operation of clinical trials by changing the spacing in time between administration of the experimental agent or drug in the volunteers to be sure no adverse effects are immediately seen. This case also became one often referred to by clinicians when explaining the “content of information documents, particularly the concept of potentially unforeseen side effects” (NIH) to their patients. In a typical Phase 2 study, there is a smaller number of subjects (100-200) and the appropriate drug dosage is determined. Phase 3 is when trials are conducted on a larger scale (500-600 participants) and efficacy is researched, and Phase 4 trials are post-marketing trials that may be conducted after the compound has received FDA approval for a particular use (Cancer.org). Pediatric studies or studies to explore the use of the compound in a condition different from the approved condition may take place here, and in aggregate, all phases of a clinical trial will typically exceed two years.
Moving on from clinical trial structure, in addition to pregnant women and fetuses (the most directly impacted stakeholders), various other parties must be considered. The biological parents of the fetus which generally consist of a mother and father are also impacted by the inclusion or exclusion of pregnant women in clinical trials. Physicians, researchers, and the FDA are also large stakeholders. I will discuss all of these parties throughout my paper, but now I would like to focus on the stakeholder of pharmaceutical companies, specifically in the context of legal liability.
According to Dr. Hester Visser, Vice President, Clinical Development at Amneal Pharmaceuticals, pharmaceutical companies have the participants’ needs prioritized. However, pharmaceutical companies also have legal liability if injury or harm is done to a trial participant, which could cause reputation damage. This risk of liability and lawsuit in the future is largely what disincentivizes pharmaceutical companies from including pregnant women in their clinical trials. On March 23, 2023, the Research with Pregnant and Lactating Persons: Mitigating Risk and Liability and Committee Meeting #2 led by the National Academies occurred and hosted a panel with Sara Dyson, Vice President of Underwriting Operations & Risk Management at Medmarc, Hillary Noll Kalay, Principal Counsel University of California Institutional Review Board Perspective, and Elisa Hurley, Executive Director Public Responsibility in Medicine and Research. During this panel and meeting, the legal liability and litigation of pharmaceutical companies were discussed, specifically focusing on why these companies might hesitate to include pregnant and lactating persons in their clinical trials. During the panel, it was mentioned that U.S. juries are very punishing to companies that cause injury to pregnant women or fetuses, leaving them with little to no chance of winning the case. One panelist mentioned that the companies should already be writing the check if sued to convey the severity of this point. This highly probable and non-ideal outcome for the pharmaceutical companies would result in great financial loss due to the legally obligated payment from the suit, and because this consequence could easily be avoided if pregnant women were not involved in clinical research in the first place, many companies make the decision to exclude pregnant women from clinical trials research to make themselves not liable for injury to fetuses or pregnant women.
John Beisner, Partner Skadden, Arps, Slate, Meagher & Flom LLP and Affiliates, also stated during the meeting that the FDA is core in clinical research litigation and that if it approves a drug and reports come in regarding negative side effects of the drug, the argument to the jury on behalf of the pharmaceutical company is that the FDA gave its approval of the drug so the company should not be liable for any injury or damage done. He also mentioned that additional studies for a drug that caused injury or harm might leave a company liable to the plaintiff’s attorney and other legal complications that it would want to avoid, which provides another reason why companies resist the inclusion of pregnant women in clinical trials.
Another point of Beisner’s was that if a fetus is injured by the drug in a clinical trial when its birth occurs, there is now an individual with lifetime limitations going forward. This is a serious problem for the company that manufactured the drug as it caused irreversible damage to an individual prior to its birth. In standard cases like this with non-fetal participants, a common defense that companies use is pointing to other factors to combat a claim against the drug, for example, if the individual was obese, the company claims that the drug could have affected them differently since the participant was not part of the demographic tested. With young children and fetuses, other factors are much harder to identify since they had lesser autonomy and were not born when the injury occurred. In summary, the potential future risk of litigation and lawsuit is a large part of what makes companies unwilling to include pregnant women in clinical research. The National Institute of Health (NIH) offers the “lack of financial incentives and the absence of a mandate for these studies to be performed prior or subsequent to FDA approval” as the explanation for why pharmaceutical companies exclude pregnant women from clinical research.
COVID-19 Vaccine Trials and Pregnancy
Shifting gears from pharmaceutical companies generally excluding pregnant women from clinical trials due to their opposition to being held legally liable for harm done, an example of pharmaceutical companies and their eventual inclusion of pregnant women was during the COVID-19 pandemic. Initially, pregnant women were not included in the clinical trials for the COVID-19 vaccine in both Pfizer’s and Moderna’s trials. Pfizer’s began in July 2020 (Pfizer) and Moderna’s began in May 2020 (NIH), but Pfizer and Moderna did not include pregnant women in these studies until February (Covid Act Now) and September of 2021 (NIH), respectively. Since then, pregnant women have been included in both companies’ vaccine trials, and this paper will review the actions of Moderna. The Moderna vaccine clinical trial which included pregnant women, or officially the “Moderna mRNA-1273 Observational Pregnancy Outcome Study”, began on September 1, 2021, has a primary completion estimate of December 9, 2023, and a study completion estimate of January 6, 2024, so the trial is not yet complete. Its estimated enrollment was 1000, its study population was “women who have been exposed the Moderna COVID-19 vaccine during the 28 days prior to their LMP or at any time during pregnancy are eligible for this exposed cohort” (NIH), and the eligibility criteria is below as stated by Moderna:
- Currently pregnant
- The outcome of pregnancy (that is, pregnancy loss or live birth) must not be known at entry.
- Agrees to electronically sign the release of medical information form permitting the study to contact her HCPs (for example, primary care provider [PCP], obstetrician, nurse midwife) and the infant’s HCP (for example, pediatrician) for medical information.
- Received the Moderna COVID-19 vaccine at any point from 28 days prior to last menstrual period (LMP) throughout pregnancy.
- Participant has received any other COVID-19 vaccines at any point from 28 days prior to LMP throughout pregnancy.
- Women currently participating in another investigational device or drug study, currently taking an investigational medicinal product, or having taken an investigational product within 28 days prior to LMP or during pregnancy” (NIH).
Initially, pregnant women were not included in the clinical trials for the COVID-19 vaccine in both Pfizer’s and Moderna’s trials.
Additionally, all participants must be 18 years of age or older and be female. The clinical trials were created to measure birth defects in the infant, the number of pregnancy complications to the mother, pregnancy outcomes (ie. stillbirth), and congenital malformations of the infant (NIH).
On August 18, 2022, WHO released a statement that “[g]iven the adverse consequences of COVID-19 during pregnancy and the increasing data supporting a favorable safety profile of mRNA-1273 in pregnancy, WHO recommends the use of mRNA-1273 in pregnant individuals”. CDC shortly followed with “CDC recommends COVID-19 vaccines for everyone aged 6 months and older, including people who are pregnant, breastfeeding, trying to get pregnant now, or those who might become pregnant in the future. This recommendation includes getting boosters when it is time to get one” on October 20, 2022. Because of pregnant women’s participation in clinical trials for the COVID vaccine, both the WHO and the CDC were convinced to encourage vaccination for the demographic. This success provides more evidence for the inclusion of pregnant women in clinical trials.
Shifting from the previous objective lens, my ethical question is whether it is ethical to exclude pregnant women from clinical trials of medications that are likely to be prescribed to or for pregnant women.
Fetal vs. Maternal Health-Which Should Be Valued More?
When conducting a clinical trial, the potential consequences to the participant are of utmost importance, as has been demonstrated by the common practice of excluding pregnant women from clinical trials due to the potential adverse effects their participation can cause. However, in clinical trials with pregnant women, there are two participant stakeholders to consider: the mother and the fetus. The maternal-fetal dyad is a term that represents the joint identity and undeniable linkage between the mother and her child in its fetal form. Originally, “the fetus was not sharply distinguished from the mother’s condition of pregnancy” (Children With Prenatal Drug Exposure 6), but in 1992, a paper was published that mentions that with modern technology the fetus no longer has to be examined through the mother but as its own entity (The Maternal-Fetal Dyad Exploring the Two-Patient Obstetric Model), thus creating two separate participants to be considered in clinical research. This raises several questions including whether, when there is a conflict between the health or treatment of the pregnant woman and the health or treatment of the fetus, which ought to take priority.
There are three primary potential outcomes for fetuses involved in clinical research: congenital malformations, pregnancy outcomes, and infant outcomes.
In order to answer this question, the health considerations and potential consequences to the fetus and pregnant mother must be evaluated. Beginning with the fetus and thinking back to the Thalidomide Tragedy, thousands of children were born with deformities as a result of the drug. The same outcome is possible with active medications tested in clinical trials if the teratogenicity is too high. There are three primary potential outcomes for fetuses involved in clinical research, as it has been proven that medication ingested by the mother can cross the placenta and affect the fetus. The first of these outcomes are congenital malformations, such as a cleft lip and spina bifida. The next is pregnancy outcomes like fetal death, stillbirth, and live birth. The last is other infant outcomes, which include low birth weight and respiratory distress. While some of these results are ideal, such as live birth, some are far from it, like stillbirth. Based on this information, it appears that there are more harmful outcomes to a fetus than beneficial ones when placing it in a clinical trial, which is part of the reason why many pharmaceutical companies and researchers may be hesitant when including pregnant women, the carriers of the fetuses, in their clinical research. Another point to mention is that these results on the fetuses do not only impact them during the gestational period but can have life-long effects, and in this case, the harm done would likely be unknown during the clinical trial stage. This could leave pharmaceutical companies and research sponsors in a difficult legal situation years after the harm occurred if the individual(s) affected decide to sue, not to mention the fetus having lived a number of years negatively affected by the trial with a certain condition. One example of this is in a Dutch study that examined if sildenafil, the generic version of the erectile dysfunction drug Viagra, could help address broncho-pulmonary dysplasia, a potentially fatal condition resulting from restricted development in utero, through increased blood flow to the placenta. The study resulted in eleven babies developing high blood pressure in the lungs and dying, but nine developed the same disorder and survived (Washington Post). These effects occurred in 2018, and as it is now 2023 they have likely persisted for five years and could have developed further, thus harming the now-child included in the trial but also causing more legal liability for the Dutch researchers. It is interesting to note that the FDA approved sildenafil in 2005 for the treatment of pulmonary arterial hypertension (PAH), and is marketed under the brand name Revatio.
Additionally, due to the status of fetuses existing in the womb of the mother and the fact that they are under the age of eighteen and can technically be considered minors, they do not have the capacity to make decisions for themselves. This leaves them vulnerable to the actions of their mother, for example, how “substances ingested by pregnant women [like their mother], such as therapeutic or recreational drugs and alcohol, may lead to harms including spontaneous abortion, stillbirth, preterm delivery, structural malformations, dysmorphic features and neurodevelopmental disorders” (Clinical Research Involving Pregnant Women 146). Because the fetus is not yet born, it has no autonomy and cannot do anything to combat the actions of its mother. Another point to mention is that certain maternal behaviors “…such as severe nausea and vomiting, may have no effect on foetuses, whereas drugs, such as thalidomide, that have limited effect on the pregnant women, may be catastrophic for the foetuses” (Clinical Research Involving Pregnant Women 146). This demonstrates that a mother and fetus cannot be considered as one entity like the maternal-fetal dyad claims, which negates the ability of the mother to be the fetus’s decision-maker. However, there is no other option than having the pregnant woman make decisions for her fetus as it is not yet born, which is why medical regulations give pregnant women that status. Medical regulations also often give pregnant women status in decision-making as they are assumed to have the best or parallel interests of the fetus always in mind.
Moral status is a “concept that deals with who or what is so valuable that it should be treated with special regard.”Encyclopedia.com
This is only one view. The issue of the moral status of a fetus is a long-debated topic that has no commonly agreed-upon resolution among ethicists, philosophers, and other individuals. It arises mainly when discussing abortion, but many arguments from it can be applied when discussing fetal status in clinical trials as well. However, before diving into these arguments, moral status must first be defined. Moral status is a “concept that deals with who or what is so valuable that it should be treated with special regard” (Encyclopedia.com), thus explicitly placing value on certain individuals more than others. Cambridge University Press and Assessment indicates that to have moral status “an individual must be vulnerable to harm or wrongdoing.” Maggie Little, BPhil, PhD, Francis J. McNamara, Jr. Chair of Philosophy, Senior Research Scholar, Professor of Philosophy, Director of Ethics Lab, of the Kennedy Institute of Ethics at Georgetown University (Kennedy Institute of Ethics) stated that “the capacity for sentience is necessary for moral status” and “[t]o say that something has such status is to say its interests intrinsically deserve protection”, which, if the fetus is determined to be sentient, it would deserve to be prioritized or at least protected to a certain degree. She also mentioned that “moral status doesn’t emerge until after the middle of pregnancy” and therefore “[a]s a partially-realized human being, the embryo has partial moral status” (Little). Continuing the prior analysis, this means that the fetus deserves protection but not to the same extent as “the human being, again a term meant here to signal paradigmatic person with full moral status” (Little) such as the mother, thus valuing the mother over the fetus. Based on the words of Little, a fetus should be granted full moral status when it becomes a human being, not a partially-realized human being. However, during the gestational period, it can be granted partial moral status. However, when does it become a full human being? This is a very difficult question to answer, but using Maggie Little’s argument, one response can be that a fetus should be accorded all the recognition and protection granted to a human person when it is deemed sentient.
Health considerations and potential consequences for the mother cannot be ignored, especially since they are the demographic that is currently alive and has decision-making capacity. Examples of pregnancy complications that can occur during clinical research are preeclampsia, eclampsia, pregnancy-induced hypertension, antenatal bleeding, preterm labor, and postpartum hemorrhage, and some pregnancy outcomes are preterm birth and maternal death. If any of these conditions are to occur, the mother or her family could sue the researchers under tort law, which Cornell University defines as “an act or omission that gives rise to injury or harm to another and amounts to a civil wrong for which courts impose liability.” However, this is unlikely as clinical trial subjects typically release the study sponsors from liability for unforeseen consequences in return for the opportunity to participate in the trial. Additionally, the occurrence would illuminate the lack of safety in the experiment, which would not be “doing good” for either the mother or fetus, since it relies on its mother for nutrients and healthy development.
Examples of pregnancy complications that can occur during clinical research are preeclampsia, eclampsia, pregnancy-induced hypertension, antenatal bleeding, preterm labor, and postpartum hemorrhage, and some pregnancy outcomes are preterm birth and maternal death.
Another viewpoint to note is that based on the experience of Dr. Visser in medical school, she and her peers were taught to value the life of the mother over that of the fetus in cases of life or death for multiple reasons, the primary ones being the fact that the mother is already living. She most likely has a partner and could have other children, and if she loses one baby, there is the possibility that she may be able to have another without complications. However, it must be noted that this is an assumption, as in many cases fertility is a struggle for many individuals, as “among heterosexual women aged 15 to 49 years with no prior births, about 1 in 5 (19%) are unable to get pregnant after one year of trying (infertility). Also, about 1 in 4 (26%) women in this group have difficulty getting pregnant or carrying a pregnancy to term (impaired fecundity)” (CDC). This assumes that any given woman easily has the ability to have another child, which would prioritize the possible “other” child instead of the existing fetus. Shifting viewpoints, Dr. Visser’s stance is supported by an anonymous mother quoted by STAT who told physicians with her partner, “I know some mothers might choose differently and I respect that. I am just not them. I have a two-year-old child home who needs me too. I want to try to save my baby…[p]lease do all you can. But if something goes wrong and if choices have to be made during the operation, I choose me.” In this quote, the mother mentions another child and the article mentions a partner, which is the mother’s reasoning for ultimately valuing her own life over that of her child. However, this does not diminish the fact that she wants to “try to save [her] baby” if possible. Additionally, if the child were to be born without a surviving mother, it may develop poorly from a lack of nurturing such as breastfeeding. It could also experience severe psychological impacts from not having a mother, such as “anxiety; depression; prolonged grief reactions; negative effects on sense of self; increased risk for suicide, substance abuse, and eating problems; difficulty with executive function; reduced quality of life” (Psychology Today).
Another point to mention is that “…as Maggie Little (2010) has noted, the focus of many guidelines tends to be on the risks associated with participation in research, which are primarily risks to the foetus, while no mention is made of the risks to the pregnant woman when the research is not performed” (Clinical Research Involving Pregnant Women 100). This implies prioritization of the fetus by researchers conducting clinical trials. From the Catholic perspective, Dr. Steven White states that “Catholic medical professionals and their pregnant patients are called to carefully discern, using the ethical framework of the principle of double effect, the interventions that may be performed to protect her life even if the unintended but foreseen consequence is the tragedy of not being able to save the life of her child (ERD 47)” (National Catholic Register). However, the initial approach is to save both the fetus and the mother. Another stance confirms this by stating that “the fact is: Catholic policy is abundantly clear on the dignity of both mother and baby, and makes no priority of one over the other” (Chicago Sun-Times). Overall, Catholicism makes no prioritization of the fetus or the mother, which complicates the situation when a choice must be made if a physician, participant, or researcher is Catholic.
Maternal illnesses such as “…high blood pressure, heart disease, diabetes, lupus, and cancer” (Clinical Research Involving Pregnant Women 100) are often what is considered when researchers make the decision to include or exclude pregnant women from a clinical trial. They consider the potential risk involved if they were to administer a drug that caused an illness, but they also must be aware that certain drugs can help treat these conditions instead of causing harm. Additionally, “…all the medicines used to treat these conditions in pregnant women are being used off-label” (Clinical Research Involving Pregnant Women 100), meaning they are being prescribed for causes different than they were created for and that the FDA approved them for. Off-label drug prescription can almost be seen as a cop-out for developing a drug specific to the needs of a demographic such as pregnant women. While not exactly an off-label prescription as it is not in the marketplace, investigating a compound in a research study for a purpose different than its original one can have harmful consequences. This was demonstrated when eleven babies died and nine suffered consequences from an off-label drug prescription of sildenafil, as mentioned earlier. However, off-label research does some good, like helping with the “prevention of repetitive abortion, inhibition of premature labor, reduction of fetal or neonatal infection, reduction in development of preeclampsia and its complications, and ripening of the cervix or induction of labor” (Off-Label Prescribing During Pregnancy). However, due to the potential harm done to the mother if she is prescribed off-label drugs, would it not do more good to synthesize a drug more catered to her specific needs?
Based on this information above regarding the consequences on both the mother and fetus, it appears that in the majority of clinical practice, the mother’s life is valued more than the fetus’. However, shouldn’t both lives be valued equally, especially since they both share the same decision-maker (the mother)? If the mother makes decisions for the fetus, will she have a conflict of interest towards saving herself over her child or vice versa? Which do mothers value more: their own life or that of their child? Is there a difference if the child is born vs. in the womb? While these are difficult questions to answer, I will provide one that might suffice: it depends. Based on the example above from STAT, the mother values her own life more than that of her child. However, the opposite can be true as well, as values are subjective.
Moving on to ethical values, I will first discuss safety. Currently, there is not enough data from randomized controlled trials (RCTs) and post-marketing data given to pharmaceutical manufacturers on the effects on pregnant women in clinical trials to properly determine/predict the safety of the mother and fetus after taking the drug. If pregnant women were always included in clinical trials, their safety has the potential to be increasingly ensured. The potential adverse outcomes of the processes involved in collecting the data can be fatal, such as maternal or fetal death or harm, because physicians and researchers have more information about the safety and side effects of certain medications and interventions on the health of non-pregnant people than they do on pregnant women. Based on this information, it would align with the principle of nonmaleficence to not include pregnant women in clinical studies, but only if not having sufficient data about the impact and safety of drugs for pregnant women is not considered a harm.
As previously mentioned, non-clinical studies are conducted on animals before clinical research occurs, which can test the teratogenicity and/or mutagenicity of a drug before it reaches the pregnant woman (Clinical Research Involving Pregnant Women 101), thus aiming to do the least amount of harm to the woman as possible and therefore aligning with nonmaleficence. Testing the drug on animals prior to the human subject provides the greatest chance of detecting teratogens and other harmful components of a drug before it enters the body of a human subject, which will decrease the risk of fatalities. Of course, animal testing does not provide 100% accuracy and there is always room for error or misjudgment, giving fatalities in clinical research and testing the opportunity to arise even still.
Additionally, not including pregnant women in clinical trials has the potential to lead to a situation similar to the Thalidomide Tragedy; a drug could be marketed to pregnant women without being tested on them and there could be harmful consequences to both the mother and child, like birth defects. The approach of learning from the past can be applied here- the developers of thalidomide did not test on pregnant women, and many mothers and neonates suffered the consequences. How would this be valuing the safety of both parties if we are unwilling to learn from our past and therefore are knowingly endangering consumers?
Pharmaceutical manufacturers are obligated to place labels and prescribing information packaged with prescription products that state the demographics the product has or has not been tested on, which provides pregnant women with the opportunity to choose whether or not to ingest a drug based on that information. This way, it would be based on comfort and self-assessment of safety. Additionally, the results of non-clinical animal studies are often displayed on the labels, which are available for viewing. Something to consider, though, is that animals are not human and they may not react in the exact way to certain chemicals or components that humans would. Nevertheless, this would be left up to the consumer to assess based on their own level of comfort. However, according to a 2014 statistic, 90 million adults are not educated enough on how to properly read and understand medication labels (United States Pharmacopeia), which could endanger them and leave them susceptible to the consequences of taking improper medication. Simply placing a label on medication that states that it has not been tested on pregnant women leaves the safety of individuals in their own hands, which may not be as medically educated as pharmaceutical companies assume. Therefore, it would do less harm to observe the effects of the drug on pregnant women in clinical research, which is a controlled environment, than to leave consumers susceptible to the consequences of their uneducated actions. The duty to warn of potential consequences falls to the physician, though, as they are responsible for educating the participant about the risks and benefits of taking a medication.
According to a 2014 statistic, 90 million adults are not educated enough on how to properly read and understand medication labels.United States Pharmacopeia
Without including pregnant women in clinical trials, accurate and safe, non-teratogenic dosages of medication cannot be determined, which could lead to fatal consequences. According to the Association of American Medical Colleges, it has been “indicated that pregnancy lowers blood levels of the anti-influenza medication Tamiflu, potentially making the standard dose too weak for pregnant women” as there has been no research on the drug’s effects on bodily changes during pregnancy such as lower blood levels. This could leave the pregnant woman vulnerable to more virulent cases of influenza, which are often fatal. Due to the gravity of the consequences, it would be more ethical to include pregnant women in clinical trials to keep them safe from external harm that could have been avoided if the proper research had been done.
Lastly, in addition to the Moderna study mentioned previously, a French study was conducted and published on February 7, 2022, concerning the perceptions of the COVID-19 vaccine by pregnant women. The women were asked a total of twelve questions, the first being “Would you agree to be vaccinated against Covid?” Out of the 664 responders, 196 answered “yes” and 468 responded “no”. Both groups provided reasoning for their responses, the “yeses” being “to protect me” (166), “to protect my relations” (156), and “to reduce the risk of Covid-19 infection in my future child” (122), and the “nos” being “I am more afraid of the side effects of the Covid vaccine on my fetus than of COVID” (360) and “I am more afraid of the side effects of the Covid vaccine on me than of COVID” (158). The study left a category for “other” as well, one of which being that there was “no specific study on pregnant women,” an option that nineteen out of the 664 participants chose (Pregnant women’s perceptions of the COVID-19 vaccine: A French survey). This provides valuable insight into how different aspects of clinical trials are weighed by mothers, which can allow researchers to alter their behavior to do more good for them.
Due to the need for data on pregnant women in clinical research, the obligation to not repeat the Thalidomide Tragedy, the risks involved with off-label prescriptions and testing, and the sentiments of pregnant women, I believe that pregnant women should be included in clinical trials.
The next value I will discuss is respect for autonomy. Pregnant women do not have the same autonomy as non-pregnant individuals if they are often barred from participation in clinical trials, as they do not have the choice to participate; they only have the option of being excluded from the trials. How is this fair to pregnant women if they do not have the same opportunity and abilities as non-pregnant women? This treats pregnancy as a handicap, which the Americans with Disabilities Act disagrees with.
“Once the embryo implants, it begins to function as part of the pregnant woman. There is no clear boundary or distinction between the pregnant woman and the foetus.”Clinical Research Involving Pregnant Women
If the mother is eighteen years old or older, she has legal autonomy over herself and can give informed consent. Despite this, not every mother is an adult, as in 2020 24% of all teen births were to mothers under the age of eighteen (HHS.gov). However, in certain states, pregnancy can emancipate a minor, like New Jersey (Murano & Roth) which can allow the mother to gain medical decision-making autonomy. In this case, for adult mothers or mothers who are emancipated, since they are carrying another being inside of their wombs that cannot give informed consent nor does it have autonomy, it can be argued that her autonomy is altered. However, it can also be discussed whether the mother has the obligation to alter certain behaviors in order to do the most good for her child. It is typically said that autonomy is limited when actions, behaviors, or choices start to harm other people, but when applied to this scenario, is the fetus “another person”? This once again raises the question of moral status that Maggie Little discusses, her stance being that the fetus has partial moral status, which makes the fetus a potential person who will go on to be a person unless an internal or external occurrence interferes with the process of development. This “occurrence” could harm the fetus, which would make the mother’s autonomy need to be limited, but it could also “do good” for the fetus, thus making the opposite necessary and creating an ethical dilemma. However, once again, is the fetus a person? The connection between the mother and fetus is demonstrated in the statement that “[o]nce the embryo implants, it begins to function as part of the pregnant woman. There is no clear boundary or distinction between the pregnant woman and the foetus” (Clinical Research Involving Pregnant Women 2). This links back to the information stated earlier in the paper regarding the maternal-fetal dyad and how actions harmful to the mother may not harm the fetus and vice versa. An example of this is alcohol consumption: ingesting alcohol may temporarily affect the body of the pregnant woman, but it can cause a baby to be born with fetal alcohol syndrome and experience physical and mental damage because of it. Based on this analysis, I have decided that due to the harm the fetus would receive because of the mother’s unlimited ability to make autonomous decisions, maternal autonomy should be somewhat limited during pregnancy, as one individual’s autonomy is typically considered to be limited by when it causes harm to another individual.
It is important for the issue of moral status to be discussed in the sense of whether the moral status of the fetus is what limits the pregnant woman’s autonomy at certain points. As mentioned earlier, Maggie Little deems a fetus as having “partial moral status” while providing enough information to make the inference that the mother would have full moral status. Through this lens, because the mother has more moral status, her own autonomy should be dominant to that of the fetus. However, because the fetus has moral status as well (albeit to a lesser degree), it has the ability to limit its mother’s autonomy, but cannot control it completely.
While it is necessary to acknowledge that pregnant and non-pregnant women may not have the same levels of autonomy, this inequality is justified to prevent the mother from doing harm to her child. In this case of autonomy, beneficence should be prioritized, and due to the designation of partial moral status for a fetus and the possible harm done to a fetus if the mother’s autonomy is not limited, the mother has an obligation to limit her own autonomy. However, the degree of this limitation will vary depending on the individual and the situation, decision, or choice being made.
Evaluating Risk vs. Benefit in Clinical Trials
I will now examine the complicated dynamic between risk and benefit in the inclusion and exclusion of pregnant women in clinical trials.
Informed consent consists of four principles: the patient must have the capacity to make a decision, “the medical provider must disclose information on the treatment, test, or procedure in question, including the expected benefits and risks, and the likelihood (or probability) that the benefits and risks will occur,” patient comprehension of the terms must be obtained, and consent must be voluntary and free of coercion (eMedicineHealth). If “patient” is substituted with “pregnant participant”, this concept can be directly related to the risks and benefits involved with pregnant women’s inclusion and exclusion in clinical trials. The pregnant woman should be able to determine the appropriate amount of risk she is willing to take for herself and her child, as both the certainty of a risk becoming a reality and the evaluation of the risk are dependent on the individual. The FDA should be able to make suggestions and certain restrictions since it has access to more data and knowledge than the average individual, but the domain left subject to the autonomy of the mother should be ultimately her own choice as she knows herself best. If given too much power, this could be a harmful example of paternalism where an organization deemed more knowledgeable takes over the participant’s autonomy in the name of their best interest. Despite this concern, the potential harm done if the FDA has decreased influence would be more substantial due to the expertise the organization offers the field of clinical research gained from years of experience. This experience established the credibility of the FDA and supports the idea that it might truly know what is in the best interest of the participant. To end, the mother should have a say regardless, but the role of the FDA should not be reduced.
Informed consent consists of four principles: the patient must have the capacity to make a decision, “the medical provider must disclose information on the treatment, test, or procedure in question, including the expected benefits and risks, and the likelihood (or probability) that the benefits and risks will occur,” patient comprehension of the terms must be obtained, and consent must be voluntary and free of coercion.eMedicineHealth
The case study entitled Our Baby, My Body pertains to a couple who is having a child during the COVID-19 pandemic. Melinda, who is pregnant, wants to live her life differently than Tom, her husband, feels is appropriate, which creates a dynamic of conflict in the relationship. Both parties feel that their decision will benefit the child the most, and the ethical question to consider with this is which course of action will do the most good for the child. Melinda’s plan consists of a fair amount of exercise and potential exposure to COVID-19 at work, as her coworkers are currently infected with the disease, which Tom disapproves of. This chance that Melinda could get infected with COVID at work could decrease her health and therefore affect the baby, which is Tom’s concern. The case does not state whether Melinda’s healthy and sick coworkers are all vaccinated and wearing masks and if they work in close proximity to each other. This dilemma is an example of weighing the benefit and risk in a situation, and in this particular scenario, it seems that the risk is outweighing the benefit, as there is too much unknown about what could benefit Melinda and her fetus, such as mask-wearing and vaccination status of Melinda and her coworkers, and too much known about the risks, such as coworkers currently infected with COVID-19. This dilemma is similar to one that clinical researchers run into with including pregnant women in clinical trials; they want to do the most good, but feel that the potential risks involving harm are too great.
Risks from untreated illness have the potential to outweigh the risks from clinical trials, for example in the Sildenafil study, if the mothers had continued to live with fetal growth restriction, would the eleven babies still have died? Would more have suffered consequences? Would nothing have happened? While nothing is definite, there is a risk in both options. The human ability to understand the risk in situations involving uncertain or unknown results is very limited, which is why pharmaceutical companies and other conductors of clinical trials are hesitant to take risks along the lines of including pregnant women in these trials. However, in order to eliminate this unknown factor, is it not necessary to gather more data and information on the responses of pregnant women in clinical research through more inclusion in clinical trials?
A point to mention is that “[e]xcluding pregnant women from particular clinical research might deny them the possible benefits of an experimental intervention (Shivakumar et al. 2011). The risks of untreated illness could be great enough to outweigh the risk posed to the foetus by research participation, especially since untreated illness itself poses health risks to the foetus (see Baylis and MacQuarrie 2016)” (Clinical Research Involving Pregnant Women 59). This conveys the idea that external factors like disease can outweigh the risks involved in clinical research, which implies that clinical research would provide the most benefit to the pregnant woman and the fetus. Personally, I agree with this and feel that risk will always be present, and there may be multiple sources of risk. It comes down to less of a benefit vs. risk dynamic and more so a risk vs. risk dynamic. Whichever risk is chosen would be the risk that would provide the most benefit or the least harm.
There will be a risk in whatever decision pharmaceutical companies and researchers make regarding the inclusion or exclusion of pregnant women in clinical trials, but what is important to note is the ability of the mother to determine risk as well. In addition to risk, uncertainty is a near-guaranteed factor to be present when evaluating benefit and risk, but what must be taken into account is the decrease of uncertainty and potential harm with more data and experimentation.
The decision to include or exclude pregnant women from clinical trials has been proven through this paper to be one of immense difficulty due to the vast quantity of ethical considerations, personal beliefs and values, and data and facts involved. The section discussing the ethics of this decision began with the question of whether safety can ever truly be ensured when evaluating the safety and pregnant women in clinical trials. Based on the earlier analysis, safety and the ideas of harm appear to be linked in the sense that pregnant women need to be included in clinical trials to reduce the potential harm done due to the lack of data on the demographic and the harm that would be done if a situation similar to the Thalidomide Tragedy were to be repeated, namely the use of untested medications by pregnant women. Off-label prescriptions, testing, and the thoughts and concerns of pregnant women are also crucial to consider along with safety due to the harm these factors have the potential to cause if ignored.
Additionally, autonomy was discussed, particularly in terms of whether or not autonomy should ever be limited. To summarize the content of this section, pregnant women should have the right to exercise autonomy, but with limits to protect their developing child from harm. A common form of these limits is the restriction of alcohol ingestion during pregnancy, but another is not going into the office when coworkers are sick with COVID-19, as occurred in the Our Baby, My Body case study. These limitations stem from the partial moral status of a fetus which grants it some control over the autonomy of its mother. Building off of autonomy was an examination of the ongoing conflict of benefit and risk in the field of clinical research, especially of who gets to determine the appropriate benefit and risk in a given situation and the potential outcomes of either decision. I have come to the conclusion that no matter how great the benefit is, the risk cannot be ignored, but this does not mean that pregnant women should be excluded from clinical trials; with everything, there is a risk, from clinical research to the Tom and Melinda case. It comes down to evaluating which risk involved will do the most good instead of finding a solution that has no possible harmful outcomes. There should also be a collaboration between pregnant women and the FDA to determine the appropriate amount of risk to take to receive the greatest amount of benefit in return. The decrease of uncertainty and potential harm with more clinical trial data is an important consideration as well to encourage the inclusion of pregnant women in clinical trials.
Overall, through my analysis of these ethical values and principles, I found that there is more evidence and reasoning in support of including pregnant women in clinical trials than excluding them, and this conclusion is the key influence in my suggestions for the future of pregnant participation in clinical research. Firstly, more clinical research involving pregnant women should be conducted, perhaps after the first trimester of pregnancy, when the risk to fetal development would likely be the least harmful. This is a simple yet substantial step towards decreasing harm done to pregnant women that has the potential to do immense amounts of good. Next, Elisa Hurley mentioned during the Research with Pregnant and Lactating Persons: Mitigating Risk and Liability and Committee Meeting #2 that having maternal-fetal medicine specialists on institutional review boards ask why pregnant women are being excluded from clinical research could help them change the standard and be included in it more frequently. I agree with this statement as having an increase in specialists on the subject of pregnancy in clinical research should also increase the amount of good done as individuals who specialize in the topic would be making decisions and offering input on regulations instead of individuals uneducated on the topic who would use general or less-researched knowledge to influence regulations. The FDA could also review its guidelines to be more inclusive of pregnant women, as noted as “a change in the language of regulations; not leaving inclusion of pregnant women in clinical research optional, but instead requiring a justification for the exclusion of pregnant women from clinical research” (Clinical Research Involving Pregnant Women 73). This constitutes a change of the norm; instead of reverting to the default exclusion of pregnant women in clinical trials without formal reasoning, implement guidelines that require written rationalization for the exclusion. This would make it more difficult for researchers to receive approval for the exclusion of pregnant women in clinical trials, thus helping promote their inclusion and the development of more knowledge about how various drugs, drug components, and interventions affect the pregnant woman and the fetus.