Perspective
Enrolling Pregnant Women in Research — Lessons from the H1N1 Influenza Pandemic
N Engl J Med 2010; 362:2241-2243June 17, 2010
- Article
The global H1N1 influenza pandemic disproportionately affected pregnant women, drawing attention to the fact that although they need safe and effective medical treatment, they have always been a marginalized study population. Antiviral agents for treating influenza have been available in the United States for more than 10 years and are widely prescribed for pregnant women. Despite the understanding that physiological changes associated with pregnancy (e.g., changes in renal and hepatic function) can markedly alter pharmacokinetics, pharmacokinetic studies have not routinely been conducted in this population. Not only could the lack of these data result in incorrect dosing and ineffective or subtherapeutic treatment for pregnant women, but inadequate dosing could also potentially accelerate the development of drug resistance and negatively affect the general usefulness of antiviral treatments during a pandemic. In the early 1990s, the Food and Drug Administration (FDA) removed restrictions on, and actually began encouraging, the inclusion of women of “child-bearing potential” in clinical studies. We would argue that it is not only permissible but also imperative that pregnant women be judiciously included in research.1,2
Pregnant women are an important study subpopulation; more than 4 million women in the United States, and 131 million women worldwide, give birth annually. A prescription-database study showed that about 64% of pregnant women in the United States are given prescriptions for one or more medications (excluding vitamins and minerals) for chronic medical conditions or for acute problems that arise during pregnancy.3 Despite these medical needs, clinical studies are rarely conducted in pregnant women. Prescribing decisions are therefore generally not evidence based, a failing that results in inadequately treated medical conditions, the exposure of the fetus to drug therapies at doses that may not even confer benefits to the mother, or treatment that carries undefined risks. For example, preliminary evidence that the higher complication rate associated with H1N1 influenza in pregnant women may be due to the use of inadequate doses of oseltamivir has led some researchers to suggest using higher doses in severely ill pregnant women infected with the H1N1 virus.4 In another example, a 2007 study (partially funded by the FDA's Office of Women's Health) suggested that serum levels of amoxicillin that are adequate to prevent anthrax may be unachievable during pregnancy because of altered renal function.5
The importance of studying subpopulations that have previously been excluded from research is undeniable. Before the passage of legislation intended to encourage pediatric research (the Pediatric Research Equity Act [PREA] and the Best Pharmaceuticals for Children Act [BPCA]), children were therapeutic orphans, as pregnant women are now. Studies conducted in the pediatric population since the enactment of these laws have shown that many assumptions that had been made about extrapolating conclusions regarding dosing, safety, and efficacy were incorrect or only partially correct; in 2008 and 2009 alone, pediatric studies conducted under the BPCA and the PREA resulted in 92 labeling changes for the pediatric use of drugs. Pediatric research is also expanding our understanding of the best ways to study vulnerable populations, to design studies that leverage preexisting data, and to determine what additional data are needed. Similar legislation for pregnant women may be appropriate if their exclusion from research cannot be otherwise rectified.
Therapeutic options for pregnant women should be informed by scientifically rigorous data on the efficacy and safety of each medication, just as they are for nonpregnant patients. Without data to guide risk–benefit assessments and prescribing information, some physicians are reluctant to recommend medications to their pregnant patients, who, in turn, are hesitant to take even necessary medications. The failure to properly treat a pregnant woman's condition can negatively affect not only her well-being, but also that of her fetus. Ironically, the effort to protect the fetus from research-related risks by excluding pregnant women from research places both women and their fetuses at greater risk from unstudied clinical interventions and may also result in a dearth of therapeutic options specifically developed for pregnant women.
Even among experts who agree that it is appropriate to study pregnant women — under certain conditions that safeguard the mother and the developing fetus — there is still debate about the timing of their inclusion in studies and the appropriateness of retaining women in clinical trials after they become pregnant. Some experts take the position that excluding pregnant women from research is actually unethical. In general, the ethical acceptability of studying pregnant women depends largely on the medical or scientific necessity of the study (e.g., it seems critical to study drugs that are already widely prescribed for use in pregnant women) and on the minimization of risks to the woman and the fetus (e.g., by focusing on marketed drugs with known safety profiles) (see Circumstances in Which Inclusion of Pregnant Women in Clinical Studies Is Ethically Acceptable).
Strategies for risk mitigation may include waiting to study pregnant women until adequate preclinical studies (e.g., developmental toxicology studies) have been completed and a safety database that includes information on nonpregnant women has been established. In addition, clinical trials involving pregnant women in which the study drug is administered as part of the protocol should include pregnancy monitoring (e.g., ultrasonography and fetal heart monitoring) and stopping criteria on which to base the withdrawal of an individual subject or early cessation of the whole trial.
Well-controlled, randomized clinical trials, the scientific standard for biomedical research, are most often used to support the claim that a drug meets the statutory and regulatory standards for efficacy and safety. For new drugs, however, participation of pregnant women in phase 3 clinical trials will require review of the study protocol and justification on a case-by-case basis. Circumstances that would argue for such participation include the study of conditions for which there are no other available effective therapies (e.g., endemic infections) and cases in which a drug is being developed specifically to treat pregnancy-related conditions.
In circumstances in which conducting randomized, controlled trials would be ethically unacceptable, there may be other methods of obtaining information about the use of pharmacotherapies in pregnant women. For example, if pharmacokinetic studies were performed in pregnant women whose physicians have already prescribed for them the drug in question, the research-related risks would be limited to those associated with the requisite blood sampling. In addition, cohort studies that enroll pregnant women who are already using a drug (e.g., exposure-registry studies that prospectively collect data on pregnancy and infant outcomes) provide opportunities for the collection of data without exposing the woman or the fetus to new research risks.
The fact that the H1N1 influenza pandemic caused higher morbidity and mortality among pregnant women than in the general population underscores the medical community's urgent need for data regarding the safe and effective use of medications during pregnancy. The complexity of studying the effects of medications in pregnant women should not stifle efforts to obtain scientifically rigorous data to guide the therapeutic use of pharmaceuticals in this population.
Correction of the underrepresentation of pregnant women in drug research is long overdue. Physicians can support these efforts by encouraging their pregnant patients to enroll in studies so that useful data can be gathered. Patients, advocacy groups, and professional organizations can raise awareness and press for needed research and policies to support the conduct of well-designed clinical studies of drugs to be used in pregnancy. Change often occurs in response to a crisis; the public health impact of the H1N1 pandemic should be the driving force in changing our culture and our thinking about conducting studies of pregnant women.
Circumstances in Which Inclusion of Pregnant Women in Clinical Studies Is Ethically Acceptable.
Randomized clinical trials
Case-by-case review for acceptability for the study
No other available effective therapies for treatment of a serious or life-threatening condition (e.g., in pregnant women with drug resistance, drug intolerance, contraindication, or drug allergy)
Pregnant women already using the drug or class of drugs in the post-marketing setting, plus an established safety profile
Drug being developed specifically to treat pregnancy-related conditions
Pharmacokinetic studies
Pregnant women using the drug for therapeutic reasons
Pregnant women enrolled in phase 3 clinical trials of a drug on the basis of therapeutic need, a circumstance in which collection of pharmacokinetic data during pregnancy should be part of the study
Exposure-registry studies*
Pregnant women using the drug for therapeutic reasons (in which case pregnant women could be classified for enrollment according to the specific drug therapy being used or the medical condition of interest)
* To learn more about, or to enroll a patient in, a pregnancy-exposure registry, see www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134844.htm.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source Information
From the Office of the Commissioner (S.F.G., B.G.); the Office of Good Clinical Practice (S.F.G.); the Office of New Drugs, Center for Drug Evaluation and Research (L.S.); the Maternal Health Team, Pediatric and Maternal Health Staff (L.S.); and the Office of Women's Health (B.G.) — all at the FDA, Silver Spring, MD.
- References
References
1
McCullough LB ,Coverdale JH ,Chervenak FA . A comprehensive ethical framework for responsibly designing and conducting pharmacologic research that involves pregnant women. Am J Obstet Gynecol 2005;193:901-907
CrossRef | Web of Science | Medline2
Coverdale JH ,McCullough LB ,Chervenak FA . The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstet Gynecol 2008;112:1361-1368
CrossRef | Web of Science | Medline3
Andrade SE ,Gurwitz JH ,Davis RL , et al. Prescription drug use in pregnancy. Am J Obstet Gynecol 2004;191:398-407
CrossRef | Web of Science | Medline4
Saleeby E ,Chapman J ,Morse J ,Bryant A . H1N1 influenza in pregnancy: cause for concern. Obstet Gynecol 2009;114:885-891
CrossRef | Web of Science | Medline5
Andrew MA ,Easterling TR ,Carr DB , et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies. Clin Pharmacol Ther 2007;81:547-556
CrossRef | Web of Science | Medline
- Citing Articles (14)
Citing Articles
1
Françoise Baylis, Scott A Halperin. (2012) Research involving pregnant women: trials and tribulations. Clinical Investigation 2:2, 139-146
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R McGready, SJ Lee, J Wiladphaingern, EA Ashley, MJ Rijken, M Boel, JA Simpson, MK Paw, M Pimanpanarak, Oh Mu, P Singhasivanon, NJ White, FH Nosten. (2011) Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. The Lancet Infectious Diseases
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Rachel REID, Daniella SUSIC, Shanthi PATHIRANA, Sally TRACY, Alec W. WELSH. (2011) The ethics of obtaining consent in labour for research. Australian and New Zealand Journal of Obstetrics and Gynaecology 51:6, 485-492
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Viviana Domínguez, Nuria Ramos, Abiguei Torrents, David García, Xavier Carné. (2011) Clinical trials during pregnancy: what has been done. European Journal of Clinical Pharmacology
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Mary A. Foulkes, Christine Grady, Catherine Y. Spong, Angela Bates, Janine A. Clayton. (2011) Clinical Research Enrolling Pregnant Women: A Workshop Summary. Journal of Women's Health 20:10, 1429-1432
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Patrick G. Clay, Raghavendra B. Adiga, Tracey A. H. Taylor, Rachael Alsup, Phillip M. Gerk, MaryPeace McRae. (2011) Postpartum Pharmacokinetics of Peramivir in the Treatment of 2009 H1N1 Influenza. Obstetrics & Gynecology 118:2, Part 2, 463-467
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Rui Moreno, Andrew Rhodes. (2011) From the bedside to the bench: How to improve the care of critically ill pregnant patients with influenza*. Critical Care Medicine 39:5, 1199-1200
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Chris Kaposy, Françoise Baylis. (2011) The Common Rule, Pregnant Women, and Research: No Need to “Rescue” That Which Should Be Revised. The American Journal of Bioethics 11:5, 60-62
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A.T. Dennis. (2011) Transthoracic echocardiography in obstetric anaesthesia and obstetric critical illness. International Journal of Obstetric Anesthesia 20:2, 160-168
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R McGready, NJ White, F Nosten. (2011) Parasitological efficacy of antimalarials in the treatment and prevention of falciparum malaria in pregnancy 1998 to 2009: a systematic review. BJOG: An International Journal of Obstetrics & Gynaecology 118:2, 123-135
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Jones, Hendrée E., Kaltenbach, Karol, Heil, Sarah H., Stine, Susan M., Coyle, Mara G., Arria, Amelia M., O'Grady, Kevin E., Selby, Peter, Martin, Peter R., Fischer, Gabriele, . (2010) Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. New England Journal of Medicine 363:24, 2320-2331
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Giuseppe Cocco, David C.C. Chu, Stefano Pandolfi. (2010) Colchicine in clinical medicine. A guide for internists. European Journal of Internal Medicine 21:6, 503-508
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P. D. Griffiths. (2010) Is pregnancy an immunocompromising condition?. Reviews in Medical Virology 20:6, 341-343
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May Ching Soh, Catherine Nelson-Piercy. (2010) Antiphospholipid syndrome in pregnancy. Expert Review of Obstetrics & Gynecology 5:6, 741-761
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