Pregnant women in clinical research

Last updated February 29, 2024

Pregnant women have historically been excluded from clinical research due to ethical concerns about harming the fetus or the perception of increased risk to the woman. Excluding pregnant women from research has also been called unethical, as it results in a scarcity of data about how therapies affect pregnant women and their fetuses. Despite consensus from bioethicists, researchers, and regulators that pregnant women should be included in clinical research, up to 95% of Phase IV clinical trials that could have included pregnant women did not, according to a 2013 review.

Ethical considerations

There are several points of concern regarding clinical research with pregnant women. Some concern is related to the idea that the fetus cannot give consent to participate in the research.^[1] Some clinical research could also result in unexpected harm to the fetus.^[2] Other concerns are that pregnant women are potentially more vulnerable to negative side effects than other populations. It has also been hypothesized that pregnant women could be more susceptible to coercion than non-pregnant adults. There is insufficient data to support either of these two latter concerns, according to a 2020 review.^[3]

Conversely, the exclusion of pregnant women from clinical research has also been called unethical. The data regarding drug use and pregnancy is scarce and of poor quality. Therefore, pregnant women do not necessarily have the same access to informed, effective healthcare as other populations.^[2]

Limiting participation

Due to complications from the drugs thalidomide and diethylstilbestrol in women in the 1960s and 1970s, the US Food and Drug Administration (FDA) enacted protections to limit reproductive-age women's exposure to substances that may cause birth defects. However, the guidelines were interpreted to exclude pregnant women from any clinical trial.^[1] Despite a 1994 National Academy of Medicine Report Ethical and Legal Issues of Including Women in Clinical Studies concluding that "pregnant women should be presumed to be eligible for participation in biomedical research", a 2013 publication noted that about 95% of Phase IV clinical trials that could have included pregnant women instead excluded them.^[3] note that this “review” is not linked to in this article and that [3] is a study about testing during an Ebola outbreak.

Effects

As a result of excluding pregnant women from clinical trials, the safety and efficacy of therapies cannot be evaluated for them. Over 80% of pregnant women are regularly prescribed therapies that are untested in pregnant populations.^[1] A study of medications approved by the FDA from 1980 to 2010 showed that 91% of medications for adults lacked data about the safety and efficacy for pregnant women, or determinations of risk to the fetus.^[2] In the case of highly lethal illnesses like Ebola and HIV/AIDS before the development of effective therapies, the exclusion of pregnant women from potentially life-saving clinical therapies results in them being "protected to death".^[3]

Promoting participation

Regulators, researchers, and bioethicists generally agree that clinical trials should include pregnant women. Because pregnancy changes the way the body metabolizes drugs, it is otherwise difficult to predict how drugs tested in non-pregnant adults will affect pregnant women. In order to treat illness in pregnant women, clinical research must involve them.^[2]

Several projects and coalitions have formed to promote the inclusion of pregnant women in clinical research. These include the Coalition to Advance Maternal Therapeutics, which consists of twenty member organizations,^[4] and the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT), a project that sought to increase the inclusion of pregnant women in vaccine trials during epidemics.^[3]

Related Research Articles

Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

Selective reduction is the practice of reducing the number of fetuses in a multiple pregnancy, such as quadruplets, to a twin or singleton pregnancy. The procedure is also called multifetal pregnancy reduction. The procedure is most commonly done to reduce the number of fetuses in a multiple pregnancy to a safe number, when the multiple pregnancy is the result of use of assisted reproductive technology; outcomes for both the mother and the babies are generally worse the higher the number of fetuses. The procedure is also used in multiple pregnancies when one of the fetuses has a serious and incurable disease, or in the case where one of the fetuses is outside the uterus, in which case it is called selective termination.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

In a clinical trial, the investigators must specify inclusion and exclusion criteria for participation in the study.

Maternal use of androgens or high doses of certain weakly androgenic synthetic progestogens (progestins) structurally related to testosterone can masculinize (virilize) the vulva of a female fetus during susceptible times in pregnancy.

Clinical research is a branch of medical research that involves people and aims to determine the safety and effectiveness (efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease. Clinical research is different from clinical practice. In clinical practice established treatments are used, while in clinical research evidence is collected to establish a treatment.

<span class="mw-page-title-main">Children in clinical research</span>

In health care, a clinical trial is a comparison test of a medication or other medical treatment, versus a placebo, other medications or devices, or the standard medical treatment for a patient's condition.

Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.

HIV in pregnancy is the presence of an HIV/AIDS infection in a woman while she is pregnant. There is a risk of HIV transmission from mother to child in three primary situations: pregnancy, childbirth, and while breastfeeding. This topic is important because the risk of viral transmission can be significantly reduced with appropriate medical intervention, and without treatment HIV/AIDS can cause significant illness and death in both the mother and child. This is exemplified by data from The Centers for Disease Control (CDC): In the United States and Puerto Rico between the years of 2014–2017, where prenatal care is generally accessible, there were 10,257 infants in the United States and Puerto Rico who were exposed to a maternal HIV infection in utero who did not become infected and 244 exposed infants who did become infected.

Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola caused by the Zaire ebolavirus. When used in ring vaccination, rVSV-ZEBOV has shown a high level of protection. Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain.

Ebola vaccines are vaccines either approved or in development to prevent Ebola. As of 2022, there are only vaccines against the Zaire ebolavirus. The first vaccine to be approved in the United States was rVSV-ZEBOV in December 2019. It had been used extensively in the Kivu Ebola epidemic under a compassionate use protocol. During the early 21st century, several vaccine candidates displayed efficacy to protect nonhuman primates against lethal infection.

There is a cure for the Ebola virus disease that is currently approved for market the US government has inventory in the Strategic National Stockpile. For past and current Ebola epidemics, treatment has been primarily supportive in nature.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.

A respiratory syncytial virus vaccine, or RSV vaccine, is a vaccine that protects against respiratory syncytial virus. RSV affects an estimated 64 million people and causes 160,000 deaths worldwide each year.

COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research, with 419 potential COVID-19 drugs in clinical trials, as of April 2021.

Atoltivimab/maftivimab/odesivimab, sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of Zaire ebolavirus. It contains atoltivimab, maftivimab, and odesivimab-ebgn and was developed by Regeneron Pharmaceuticals.

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

<span class="mw-page-title-main">Nirmatrelvir/ritonavir</span> Antiviral combination medication

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.

References

1 2 3 Heyrana, Katrina; Byers, Heather M.; Stratton, Pamela (2018). "Increasing the Participation of Pregnant Women in Clinical Trials". JAMA. 320 (20): 2077–2078. doi:10.1001/jama.2018.17716. PMID 30422300. S2CID 53293199.
1 2 3 4 Van Der Graaf, Rieke; Van Der Zande, Indira S. E.; Den Ruijter, Hester M.; Oudijk, Martijn A.; Van Delden, Johannes J. M.; Oude Rengerink, Katrien; Groenwold, Rolf H. H. (2018). "Fair inclusion of pregnant women in clinical trials: An integrated scientific and ethical approach". Trials. 19 (1): 78. doi: 10.1186/s13063-017-2402-9 . PMC 5789693 . PMID 29378652.
1 2 3 4 Edwards, Kathryn M.; Kochhar, Sonali (2020). "Ethics of Conducting Clinical Research in an Outbreak Setting". Annual Review of Virology. 7 (1): 475–494. doi: 10.1146/annurev-virology-013120-013123 . PMID 32212920.
↑ Malhamé, Isabelle; d'Souza, Rohan; Cheng, Matthew P. (2020). "The Moral Imperative to Include Pregnant Women in Clinical Trials of Interventions for COVID-19". Annals of Internal Medicine. 173 (10): 836–837. doi:10.7326/M20-3106. PMC 7384266 . PMID 32598164.

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[Heyrana-1] 1 2 3 Heyrana, Katrina; Byers, Heather M.; Stratton, Pamela (2018). "Increasing the Participation of Pregnant Women in Clinical Trials". JAMA. 320 (20): 2077–2078. doi:10.1001/jama.2018.17716. PMID 30422300. S2CID 53293199.

[Van_Der_Graaf-2] 1 2 3 4 Van Der Graaf, Rieke; Van Der Zande, Indira S. E.; Den Ruijter, Hester M.; Oudijk, Martijn A.; Van Delden, Johannes J. M.; Oude Rengerink, Katrien; Groenwold, Rolf H. H. (2018). "Fair inclusion of pregnant women in clinical trials: An integrated scientific and ethical approach". Trials. 19 (1): 78. doi: 10.1186/s13063-017-2402-9 . PMC 5789693 . PMID 29378652.

[Edwards-3] 1 2 3 4 Edwards, Kathryn M.; Kochhar, Sonali (2020). "Ethics of Conducting Clinical Research in an Outbreak Setting". Annual Review of Virology. 7 (1): 475–494. doi: 10.1146/annurev-virology-013120-013123 . PMID 32212920.

[4] Malhamé, Isabelle; d'Souza, Rohan; Cheng, Matthew P. (2020). "The Moral Imperative to Include Pregnant Women in Clinical Trials of Interventions for COVID-19". Annals of Internal Medicine. 173 (10): 836–837. doi:10.7326/M20-3106. PMC 7384266 . PMID 32598164.

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