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Transforming Clinical Trials

By Study NeedBy Study Role

April 12, 2023

Why We Need Clinical Research for Pregnant Patients

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      Aoife Delany

      Aoife Delany

      Lead Clinical Information Designer


    In recent years there have been increasing calls from the medical community to encourage the participation of pregnant and breastfeeding patients in clinical trials. Every day 12,000 newborns and 800 pregnant patients die from largely treatable and preventable pregnancy complications.

    Lack of research has led to a veritable data chasm for pharmaceutical interventions during pregnancy, with only two medicines developed specifically for pregnancy related conditions in the last 40 years. As a result, patients and clinicians are left in limbo with limited or non-existent data to help them make important decisions regarding medications for new and pre-existing conditions during pregnancy such as epilepsy, asthma and bipolar disorder.

    Despite the data chasm, 90% of patients take at least one medication during pregnancy, often being left with no choice but to roll the dice on the potential safety risks for themselves and their unborn child.

    So how did we end up here?

    History Holding Back Research

    From a historical perspective, patients assigned female at birth (AFAB) have generally been excluded from clinical research. Shockingly, there have even been studies specifically designed for AFAB issues that exclusively enrolled biological males!

    Male was considered the default model for clinical research, with experts citing hormonal fluctuations and their potential for drug interference as the reasoning for excluding biological women. Following the devastating birth defects caused by Thalidomide in the 1950s and 1960s (a drug that was never tested in humans prior to rollout), a culture of protective avoidance arose to safeguard pregnant patients and gestating babies against similar outcomes in future clinical investigations.

    In 1977, the Food and Drug Administration (FDA) issued guidelines to exclude all subjects of childbearing potential from the early phases of most clinical studies to safeguard patients. These guidelines, however well intentioned, effectively sequestered pregnant patients in bubble wrap and prevented decades of vital research.

    Despite this ban being ultimately reversed, clinicians are yet to truly embrace pregnant patients as potential research participants. Trials that have been conducted mainly focus on labor induction, abortion, and prevention of obstetric and fetal conditions, but fail to truly advance our knowledge of safe pharmacological intervention in pregnancy.

    Most recently a lack of research has created a barrier in uptake of the vaccine against COVID-19 in pregnant patients, spurring many researchers to call for greater inclusion of this cohort in clinical studies.

    Modern Barriers to Inclusion

    The medical community acknowledges that we desperately need to conduct clinical research in pregnant patients, but barriers to inclusion persist. Whilst regulatory bodies have encouraged the inclusion of pregnant patients since the early 2000s, their guidelines are ambiguous, leaving institutional review boards (IRBs), researchers and drug companies highly hesitant.

    The fear of litigation and compensation pay-outs for damage to the baby in utero (which have been as high as £37 million in the UK and $110 million in the US) make it extremely difficult to fund and insure studies of pregnant cohorts.

    In addition to researcher reluctance, patient hesitancy to participate and overall distrust in the process are perhaps the most difficult barriers to surmount. The natural parental instinct to protect is unparalleled; if there is even the slightest risk to the baby, prospective parents will hesitate. Rising numbers of patients who have struggled with infertility may make patient enrolment even more difficult for fear of harm to their much longed-for baby.

    Similarly, pregnant transgender and gender non-conforming patients may also be reluctant to participate due to complexities that prior testosterone treatment may pose to their pregnancy and future fertility, not to mention the well-recognized healthcare inequities experienced by those identifying within the LGBTQ+ community.

    Whilst patient concerns are warranted given the mistakes of the past, obstetric research is vital to safeguard them in the future - particularly with increasing diversity in pregnant populations and new medical challenges emerging every day. Interestingly, despite participation reluctance, a recent study reported that pregnant patients and their spouses paradoxically agree that we need clinical research in pregnant populations.

    So how might we attempt to overcome this impasse?

    Strategies for Inclusion

    Risk Reduction & Benefit Promotion

    As risk insurance creates such a huge barrier to pregnancy research, efforts should be made to de-risk clinical investigations. Data from previous studies largely influences insurance rates for trials, so without a pool of pregnancy specific studies to generate data for risk assessment, premiums are likely to remain high.

    A recent report in the UK suggests short-term government partnerships to co-insure trials that generate this data pool could ultimately de-risk clinical research in pregnancy. Pediatric trials were de-risked in a similar manner following a number of initiatives to increase clinical trials in this population.

    When considering patient eligibility and trial viability, insurers, sponsors, and regulatory bodies often tend to focus on fetal risk, forgetting that there are two patients in question. With risk goggles on, the potential benefits for one or both patients can be overlooked. Explicit information on how benefits outweigh risks in trial proposals needs to be prioritized to help ensure research gets the green light. This strategy was used to great effect during the pandemic in ensuring that pregnant patients were enrolled in the RECOVERY trial to find treatments for adults hospitalized with Covid-19.

    Campaign for Inclusion & Research Investment

    The wider research community in general does not understand the importance of including pregnant patients in trials to ensure safe access to treatment. This was especially evident during trials for the COVID-19 vaccine – pregnant patients were excluded, but paradoxically encouraged to take the vaccine. Trials are now being conducted after rollout in this cohort.

    As such, we need to properly educate researchers and clarify existing regulations to campaign for inclusion of pregnant patients in trials. Moreover, research investment in obstetrics is vital to overcoming current barriers. Currently in the UK for every £1 the NHS spends on pregnancy care, only 1p is invested in related research.

    We know so much about human biology, but due to this lack of research we are only at the tip of the iceberg in our understanding of reproductive physiology. Animal models are often poor, so it can be difficult to predict real world outcomes.

    However, technological advances in recent years have seen, better virtual biometric models as well as the generation of “mini organs” which with the right investment, will allow researchers to more reliably predict the interaction of drugs across the placenta. With an effective campaign, we can incentivize research investment in this area to encourage drug companies to give attention to pregnancy specific medications.

    Engage with Patients

    Pregnancy is a vulnerable time, and patients are nervous for both themselves and their unborn baby. Clinical research is largely being negatively presented to them online and in the media, so their concern is understandable. However, pre-clinical research and regulations have changed dramatically since the Thalidomide tragedy, making it much easier to predict the risks that may occur during a trial.

    If patients are properly engaged with and educated about the risk-benefit ratio for clinical trials, this may help reassure them and overcome their reluctance to participate. An excellent example of this can be seen in HIV research in pregnancy where multiple clinical trials and drug investigations have been conducted in this population to prevent disease transmission during pregnancy.

    Community engagement has been critical to success in HIV research. Advocates and trial participants are treated as partners in the process and not mere subject numbers on a clipboard. Patients are more far more involved in the process as a result due to increased transparency and understanding of the overall process. If we were to apply this model for all potential drug trials, patients may be far less hesitant to enroll in clinical research.

    Adapt Trial Designs for Pregnant Patients

    Simple modifications to trial design in non-obstetric studies may make trials more accessible for pregnant participants. The recent SNAP study, exploring Staphylococcus aureus infections in the bloodstream, made specific adaptations to the randomized clinical trial protocol to enable the enrollment of pregnant patients. As this is a common peripartum infection, specialized interdisciplinary groups with expertise in pregnancy and infectious diseases were set up to formulate pregnancy specific recommendations for the trial design, including an entire appendix dedicated to pregnancy. The investigational drugs were individually assessed for safety in pregnancy and additional safety monitoring was recommended for other drugs that may interact with the liver. Pregnancy specific outcomes were also assessed in the study.

    These simple modifications allowed this study to gain funding and regulatory approval for the inclusion of pregnant patients, allowing them to safely contribute to this research to improve future patient outcomes.

    Protecting Pregnant Patients Through Research

    All doctors take the Hippocratic oath to do no harm, but it is wrong to assume that avoiding research in pregnant patients causes no harm. While the inclusion of pregnant patients in clinical research is not without risk and should not be conducted lightly, the dangers of using medicines during pregnancy without proper investigation may pose an even greater threat. If we work together through education, research investment, trial design adaptation and engagement with patients, we can help to protect pregnant patients through research – not from it.