key: cord-313924-3swrn1rv authors: Einav, Sharon; Ippolito, Mariachiara; Cortegiani, Andrea title: Inclusion of pregnant women in clinical trials of COVID-19 therapies: what have we learned? date: 2020-05-31 journal: Br J Anaesth DOI: 10.1016/j.bja.2020.05.020 sha: doc_id: 313924 cord_uid: 3swrn1rv nan admission for 9% of pregnant women 3 . There have been also case reports of severe COVID-19 related cardiomyopathy, multiorgan failure and deaths in pregnant women 4 5 . As the COVID-19 pandemic spreads globally, an increasing number of patients are receiving experimental treatments, some within the framework of randomised controlled trials, and others as off-label or compassionate use. Off-label or compassionate drug treatment is A recent editorial on drug use during pandemics stated that the "tragedy of not discovering new therapies during an outbreak cannot be repeated" 8 . It also elaborated that "By participating in an RCT, both patients and clinicians can benefit from the unique opportunity to directly contribute to the discovery of new therapies". However, there is ongoing tension between the bioethical and research consensus that pregnant women should be included in clinical trials and actual implementation of such inclusion in a reality where one in four medical lawsuits may be an obstetric case. We studied the approach towards recruitment of pregnant women to interventional clinical trials for COVID-19. To this end we searched the US National Library of Medicine registry (Clinicaltrial.gov) for studies including the terms 'COVID OR coronavirus OR SARS-COV-2' up to 15 th April 2020. Overall 630 registered trials were identified. After applying a filter for study type ('interventional' trials), we identified 401 trials which were retrieved and screened. Duplicate trials, withdrawn or suspended trials and trials unrelated to the COVID-19 pandemic were excluded. The data on the final 371 included trials are presented in the table (Table) . Among the 371 interventional trials registered, most declare pregnancy an exclusion criterion (251/371, 68%). This is most striking in trials investigating the use of drugs (235/310, 75.8%). Many trials altogether avoid mention of pregnant women in their inclusion/exclusion criteria (117/371, 31%). Several trials (including those on the use of chloroquine) suggest referring to "known" contraindications in order to determine whether a pregnant patient may be included. This tactic effectively deflects all responsibility (and liability) to the clinician. Even trials investigating drugs with a relatively favorable safety profile (e.g. ascorbic acid), interventions or drugs already being used in pregnant women (e.g. ECMO, steroids) or those investigating low-risk non-pharmacological interventions (e.g. biological sampling for diagnostic/basic science purposes) exclude pregnant women. Most importantly, there is a global lack of differentiation between the risk at various developmental stages of pregnancy (Table) . A commonly cited excuse for non-inclusion of pregnant women in clinical trials is that pregnant women would be unwilling to participate. Adult women and their families should not be patronized because they are pregnant; they should be given the choice to participate. They may be willing to participate if the intervention is presented favourably, it is not available outside the trial and when their contribution to scientific research is highlighted. As with any other patient, fulfilment of inclusion/exclusion criteria and informed consent are mandatory to safeguard the patient. On the one hand, experimental drugs are being used to treat pregnant women with COVID-19 anyway 2 5 . On the other hand, pregnant women with COVID-19 are dying, perhaps with no treatment attempted. Declarations regarding the need to include pregnant women in clinical research and obvious concerns for the wellbeing of this population time and time again fail to translate to actual practice. What should we learn from this situation? Clarification of the approach to pregnant women should be mandatory during trial registration. Trials excluding pregnant women should be required to justify doing so. Referral to alternative sources with regards to risk should not be allowed. Industry should be expected to cover insurance for all patients, including pregnant women. In the specific context of the COVID-19 pandemic, experimental treatments offered to deteriorating patients within the context of a clinical trial in the hope that they may be of benefit should also be offered to pregnant women who deteriorate. We could learn much from the management of pregnant women whose lives are at stake during this pandemic wave. This opportunity should be embraced lest we need to explain to our daughters why we have learned nothing of use to them during this pandemic wave when they are pregnant during the next pandemic. The authors have no conflicts to declare. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies Mode of Delivery and Clinical Findings in COVID-19 Infected Pregnant Women in Northern Italy (3/24/2020) Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics We would like to thank Hen Y Sela and Carolyn Weiniger for sharing with us their insights on the topic.