December 16, 2020

expert reaction to opinion piece on pregnant women and COVID-19 treatment trials

An opinion piece published in The Lancet Global Health calls for the inclusion of pregnant women in COVID-19 treatment trials.

Dr Allyah Abbas-Hanif, Member of the Paediatrics and Pregnancy Expert Group of the Faculty of Pharmaceutical Medicine, said:

“This systematic review offers a descriptive analysis of populations represented in COVID-19 clinical trials until June 7th 2020. The article reminds us that regulators, medical societies and NGOS have rebuked the vulnerable classification often used to exclude pregnant women from investigational trials. However, emergent data has suggested that pregnant women are at increased risk of severe COVID-19 compared to age matched non pregnant women and thereby that inclusion into trials of potential therapies is important. As pregnant women may have increased risk of serious outcomes, mechanisms to accelerate novel drug development, including vaccines, repurposed agents and novel therapies for use in pregnant women are important, and steps should be taken to accelerate studies in this population. Many trials of repurposed agents have used treatments with established safety in use in pregnant women, thus the exclusion of this population from studies incorporating agents already known to be safe in pregnancy is inexplicable. The early completion of developmental and reproductive toxicity (DART) studies may enable earlier recruitment of pregnant women in trials of novel agents and vaccines. Reproductive studies are underway with Pfizer and BioNTech’s BNT162b2 mRNA vaccine, and early investigation of this vaccine in pregnant women should be possible. Many other vaccines in development have similar mechanisms of action. Extrapolating data from women of childbearing age in clinical trials and those who become pregnant also offers invaluable insights; 49.4% of the BNT162b Phase 3 trial were women and as of the 14th November 2020 datacut, 23 participants had reported intercurrent pregnancy, outcomes of which are actively being followed. Pregnant women must have access to investigational clinical trials and with careful earlier investigation and increased attention, potential risks to mother and baby may be mitigated to enable full participation in studies which may be of benefit.”

Prof Richard Haynes, Clinical Coordinator for the RECOVERY trial, said:

“It is essential that pregnant women are included in trials of treatments (for COVID-19 and other conditions), as in RECOVERY, wherever possible. There are many treatments which are known to be safe in pregnancy (or which are very likely not to harm the unborn child e.g. anti-coronavirus monoclonal antibodies). Because of the real risk of harm from COVID-19 to both mother and child, there is a strong argument to include pregnant women to help understand the risks and benefits of treatment, not only on COVID-19 related outcomes but also pregnancy-related outcomes. The alternative is clinical practice which has no evidence to support it which puts mothers and babies at higher risk and does not learn.”

Dr Catriona Waitt, Reader in Clinical Pharmacology at the University of Liverpool, said:

“The issue of inclusive clinical trials is an important one: women are not as well-represented in research as they should be. More women should be involved with research, and more pregnant women should be too. This is about making sure research is representative of people who need the benefit – and to identify risk factors for particular groups. At the same time, I think we need to take a cautious approach particularly with novel compounds and where the actual risk vs benefit for that pregnant woman and infant might be less clear. Decisions will also be influenced by the risk posed by the disease itself.

“For example, during the Ebola outbreak, pregnant women would almost all die without treatment – and all newborns died. However, pregnancy is not a massive risk factor in COVID-19 – the issue is more to do with ventilation being more challenging in late pregnancy, should it be required. Therefore, for Ebola, it made sense to take greater risks earlier – whereas for COVID-19 it is preferable to wait until more is known about the general risk profile of a novel drug or therapeutic before giving it to pregnant women.

“However, if a drug is known to be safe in pregnancy there is really no reason at all to use pregnancy to exclude women from research. But for other drugs, I would want to look carefully at risk:benefit analysis for each before making the blanket statement that pregnant women should be included automatically. This is something our research group has considered in detail for HIV[1], and I think the lessons apply here.”

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747006/ 

Prof Lucy Chappell, NIHR Research Professor in Obstetrics, King’s College London, said:

“This article highlights the concerning tendency of trials of therapeutic interventions for covid-19 to exclude pregnant women, without appropriate consideration of the need for effective treatments in this group. The authors outline that many of the proposed interventions have been used for other indications in pregnancy, and can be safely included in trials, sometimes with minor modifications.

“The RECOVERY trial is considered to be the largest trial in the world evaluating treatments for covid-19 in hospitalised patients, with nearly 21,000 participants to date. This landmark trial has included pregnant women since inception; all results published to date on use of steroids, hydroxychloroquine, lopinavir-ritonavir and azithromycin included pregnant women in their reports, changing clinical practice and guidelines as a direct result.

“The need to address equity of access for pregnant and breastfeeding women in trials of covid-19 therapeutic interventions and vaccine is clear. This article should provide further evidence that collaboration across disciplines is essential, with a clear message for inclusion of pregnant women unless otherwise fully justified.”

Dr Luke Allen, GP Academic Clinical Fellow, University of Oxford, said:

“Whilst it is easy to understand why drug companies, trial leaders, and ethics committees might be nervous about including pregnant women in studies, the truth is that leaving them out actually compounds the problem, as we will not know whether emerging covid treatment options are effective for this special group. The situation is especially damnable when trials are testing medicines and vitamins that are already known to be safe.”

Prof Neena Modi, Professor of Neonatal Medicine, Imperial College London, said:

“It is a good press release. There is long-standing recognition of the marked gender inequity experienced by pregnant women in relation to research. Pregnant women and their unborn babies continue to be denied the right to benefit through research participation. The issue is important because pharmacokinetics, pharmacodynamics, safety profiles and toxicity differ between pregnant and non-pregnant women. Without testing in populations that will receive the medications, their efficacy and safety cannot be assumed, nor will there be adequate data on dosing.

“The long-standing exclusion from such research has its origins in the research abuses of the first half of the last century which led to a paternalistic assumption that women (all women) should be considered (with children) a “vulnerable group” in need of special “protection” from the dangers of research. In addition there was recognition of the possibility of adverse fetal effects from drugs taken in pregnancy. Many groups have since questioned this well-intentioned, but nonetheless paternalistic attitude. Recent decades have also seen the evolving recognition of clinical research as an integral component of good patient care. In this, patients have a right to be protected (from non-evidenced practice) “through research”, as opposed to protected from (the dangers) “of research”. Thus, the exclusion of pregnant women has also meant that evidence of efficacy, safety, pharmacokinetics and pharmacodynamics in them has been lacking, leaving them vulnerable to harm, instead of providing protection.

“Pregnant women with SARS-CoV-2 Infection are more likely to require intensive care admission, ventilation, and die^1.

“Research sponsors are less willing to provide indemnity to cover the inclusion of pregnant women in clinical trials.

“Pregnant women are fully capable of providing informed consent to participate in clinical trials.

“I have raised this issue in relation to COVID-19 vaccines in my capacity as president of the UK Medical Women’s Federation with the UK vaccine Task Force, NIHR, HRA and MHRA.

“The solution is for research regulators to require the inclusion of pregnant women (and women and children) as the default in medicines and vaccines studies unless there are clear scientific reasons that justify their exclusion; i.e. a presumption of inclusion (as opposed to exclusion); without this sex and age based research inequities will continue.”

1. Zambrano LD, Ellington S, Strid P, et al. Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status – United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(44): 1641-7

‘Inclusion of pregnant women in COVID-19 treatment trials: a review and global call to action’ by Taylor et al. was published at 23:30 UK time on Wednesday 16^th December 2020. 

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Dr Allyah Abbas-Hanif: “No COI.”

Prof Richard Haynes: “Clinical Coordinator of RECOVERY. No other declared interests.”

Dr Catriona Waitt: “no conflicts.”

Prof Lucy Chappell: Leads the pregnancy sub-group for RECOVERY

None others received.