Pregnant women are still therapeutic orphans

“The pregnant woman is perhaps the last true therapeutic orphan. Because of the ethical, medicolegal and foetal safety concerns regarding pregnant women, few pharmacokinetic, pharmacodynamic or clinical trials are conducted during pregnancy.” Stika and Frederiksen ¹ made this observation about the lack of research on drug safety and efficacy in pregnant women in 2001.

In 2010, the US National Institutes of Health (NIH) published a report including this insightful comment: “There is so much we still do not know about how to treat pregnant women with health problems effectively and safely and how to prevent poor pregnancy outcomes. Clinical research could help provide that information. Yet, there remains a literally unhealthy reluctance to include pregnant women in clinical trials.” ²

Regrettably, these statements remain true today. In the US, a trans‐governmental task force was charged with reviewing the gaps in knowledge about safe and effective therapies for pregnant and lac‐tating women. The task force considered ethical issues raised by their enrolment in clinical research, reviewed existing investigations, produced recommendations to develop therapies, and considered effective commu‐nication strategies with health care pro‐fessionals and the public. A striking state‐ment in this document bears emphasizing: “A central theme resonated throughout the re‐commendations – the need to alter cultural assumptions that have significantly limited scientific knowledge of therapeutic product safety, effectiveness, and dosing for pregnant and lactating women. The cultural shift is necessary to emphasize the importance and public health significance of building a knowledge base to inform medical decision making for these populations.” ³

The societal motivation to protect pregnant women is powerful, but it must be aligned with their health and well‐being. Pregnant women would be far better served by changing the conceptual framework from protecting them from research to protecting them through research. Excluding pregnant women from clinical trials limits medical knowledge for this population, which is discriminatory and dangerous. Allowing pregnant women to participate in research would ultimately contribute to protection of the population of pregnant women in the future.

The majority of pregnant women take at least one medication to treat a maternal condition. The average number of medications (excluding vitamins) used in pregnancy increased from 2.5 in 1976‐1978 to 4.2 in 2006‐2008, when 93.9% of pregnant women took at least one medication ⁴ . Despite these facts, evidence to guide effective drug treatment of pregnant women is largely lacking. A limited number of drug labels approved by the US Food and Drug Administration (primarily antiretroviral and anticonvulsant agents) include information about dose changes in pregnancy. However, the frequency and magnitude of plasma concentration changes across pregnancy is unknown for the majority of medications.

The significance of this lack of data was demonstrated by the recommendation that pregnant women exposed to anthrax via bioterrorism take the antibiotic amoxicillin prophylactically. Subsequent pharmacokinetic studies revealed that plasma concentrations of this antibiotic would have been inadequate to protect pregnant women, because the physiology of pregnancy increases its clearance ⁵ .

Notably, the NIH Adaptive COVID‐19 Treatment Trial, a multinational double‐blind placebo‐controlled trial to evaluate the safety and efficacy of antiviral agents in hospitalized adults, excluded pregnant and lactating women.

The culture shift we need is supported by careful consideration of core health care ethical standards ⁶ . Non‐maleficence is the principle of not causing harm to others. The mantra of “do no harm” is often invoked by practitioners as a rationale for withholding medications from an individual pregnant woman. Discomfort with responsibility for the potential harm to the foetus through drug exposure (the error of commission) is typically greater than for the harm of not prescribing medication to the pregnant woman, on whose health the foetus depends (the error of omission). The justification for not treating pregnant women also includes inadequate data to determine the benefits and harms of treatment, which creates a perpetual cycle of health disadvantage across time.

The principle of beneficence involves conceptualizing harms more broadly: creating knowledge that advances pharmacological care for pregnant women in the future benefits the population of these women. The principle of respect for auto‐nomy implies the prioritization of patient decision‐making for health care: who sets the boundary between the pregnant woman deciding for herself about research participation or a governing body that puts limits on the research that may be done with her? The final principle, justice, requires a fair distribution of benefits, risks and costs. Pregnant women unfairly pay for society's concern about harm to their foetuses. Barring these women from research participation violates the spirit of non‐discriminatory access to advancing their health care.

Paradoxically, in the US, protectionism appears to end when the umbilical cord is cut. Mothers and newborns become social orphans. Much of our public policy suggests that maternal and infant health is a private matter for women to manage, rather than one of collective importance or governmental concern. The US Cen‐ters for Disease Control and Prevention reported that 55% of women of reproductive age in the country live in poverty – a clear adverse exposure.

The US is the only industrialized country that does not allow paid parental leave. Maternity leave is a critical factor in promoting maternal‐infant attachment, improving health and behavioral outcomes for the mother‐infant pair, and supporting breastfeeding. Paid leave and longer duration of leave (>12 weeks) reduces the adverse impact of early return to work after childbirth and is associated with improved mental health outcomes, especially among mothers working full‐time ⁷ . Once back to work, many mothers do not have sick pay available, and childcare is unaffordable. The implicit message of these policies is that a woman's value is as a unit of business: she is responsible financially for the inconvenience of her absence from revenue‐producing work due to childbirth and caring for her infant.

Another needed conceptual shift is op‐timizing the mental health of pregnant women rather than reducing symptoms of mental disorders. Positive mental health is a distinct construct, separate from the absence of disease, that is associated with improved birth outcomes and parenting practices which support favorable child development ⁸ . Emotional well‐being is an overall positive state of emotional tone, life satisfaction, a sense of meaning and purpose, balance, and ability to pursue personal goals ⁹ .

The quality of the foetal and childhood biopsychosocial milieu during the plastic early development phase is one of the de‐terminants of the risk for diseases through the life cycle. For this reason, mental health of pregnant women and mothers must be optimized. For many of these women, health is optimized with pharmacother‐apy.

Mental health professionals must insist on policies that improve the health of our pregnant and mothering patients. Through partnerships with visionary leaders internationally, we must consolidate and share responsibility for advancing treatment research for pregnant women with psychiatric illness and other medical disorders. In doing so, we will honor the extraordinary gift of newborns by caring for the women who create and nurture our next generation. We must adopt our orphaned pregnant women into the mainstream of health care research and practice.