Obstetrical complications, often referred to as the “great obstetrical syndromes,” are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.
Introduction
Obstetrical complications such as hypertensive disorders, small for gestational age, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and placental abruption, often referred to as the “great obstetrical syndromes,” cause high mortality and morbidity in young women and their newborns or infants and are lacking appropriate treatments.
The most prevalent of these syndromes are hypertensive disorders and premature births, each affecting globally more than 10 million women annually, leading to approximately 70,000 maternal and 1 million perinatal or infant deaths. The risk of dying from maternal complications disproportionately affects women in low- and middle-income countries and communities, where not only appropriate treatments are missing but also access to quality care is problematic. , Next to these extrinsic factors, it is also suggested that genetics play a role in ethnic disparity for obstetrical syndromes, indicating a potential need for ethnic-specific evidence-based care. In the United States, the maternal mortality rate remains relatively high with an increased risk for non-Hispanic Black women compared with other ethnic groups and for women aged ≥40 years. , In parallel to the increased prevalence of cardiovascular diseases among women of reproductive age, hypertensive disorders of pregnancy have also increased over recent decades, affecting approximately 10% of pregnancies and accounting for about 6.6% of maternal deaths.
Clinical presentations of obstetrical syndromes are heterogeneous, and multiple common etiologies complicate the diagnosis. Most have a long asymptomatic phase between the start of the pathologic process and the onset of clinical signs or symptoms. Disease manifestations are adaptive over the course of pregnancy, with varying fetal involvement, that depend more on the nature and timing of the pathologic disruption rather than on the etiology. In this context, early treatment in the latent period would be more beneficial.
When confronted with these complex pregnancy diseases with potentially serious consequences, obstetricians use empirical rather than robust scientific evidence for diagnosis and case management. The focus is on immediate outcomes, often juggling between unpredictable syndrome progression and prematurity risks, to decide on the optimal timing of birth. In addition, recent evidence has shown that obstetrical syndromes are associated with harmful maternal and child effects later in life. It is still unknown whether a cardiovascular disease predisposition increases the risk of preeclampsia or vice versa. The intrauterine environment may also play a role in fetal gene expression, and during obstetrical syndromes, epigenetic changes may lead to postnatal development of cardiovascular and metabolic diseases. Therefore, preventive treatment of these syndromes may have important long-term health benefits.
The Problem
Recent decades have witnessed little progress in research and development (R&D) to reduce the impact of pregnancy complications (ie, obstetrical syndromes). Only few drugs have been approved for obstetrical use, and the pipeline for novel “pregnancy medicines” looks bleak. There are about 50 interventional phase 2 trials for “pregnancy complications” listed in ClinicalTrials.gov , but all trials are small academic trials testing repurposing of drugs approved for other indications. Therefore, in obstetrics, women and their infants will not benefit from effective, safe, and approved medications in the next decade.
In contrast, over-the-counter or prescription drugs are commonly used during pregnancy, despite well-known cases of major congenital anomalies associated with medications later classified as teratogenic. , More than 60% of pregnant women use at least 1 medication either as a continuation of preexisting therapy or as a new treatment prescribed during pregnancy. This is off-label use in the absence of safety and efficacy data from studies in pregnant women.
Why is There No Progress in Pharmaceutical Research and Development?
The reason for the lack of drug research in the field of pregnancy is multifactorial. The pharmaceutical industry faces an uninviting environment with large and high-risk investments for a drug candidate compared with other medical disciplines. Although obstetrical syndromes represent a high economic burden to society, the probability that 1 approved drug will provide a positive return on investment is not guaranteed. Other obstacles include slow recruitment for the required sizable trials, which is hindered by use of a placebo comparator, lack of consensus on diagnostic criteria, demanding trial procedures, ethics committee requirements, and risks of aberrant fetal consequences with high potential for litigation. Moreover, predefined regulatory pathways are missing for most obstetrical conditions to plan for a successful product approval.
Incomplete Understanding of the Pathophysiology
The pathologic mechanisms underlying obstetrical syndromes are not fully understood. These syndromes are specific to humans and, in many of these conditions, are a result of physiological transformation abnormalities at the maternal and fetal interface, resulting in inadequate placental development and function. Moreover, it has been suggested that some epigenetic changes resulting from the complex interactions between the maternal and fetal genomes and the environment are disrupting placentation early in pregnancy, , , potentially leading to impaired vascular remodeling during trophoblast invasion and defective deep placentation. The specific etiologic factors underlying these defects are multiple and remain largely unknown. Consequently, finding the right therapeutic drug target that will modify the course of the disease represents a major challenge.
Because of the lack of truly translational preclinical disease models (see below), the beneficial effect of a new mechanism of action can only be demonstrated in pregnant women with intrinsic maternal and/or fetal risk. Mitigating such risks requires a carefully designed clinical development plan, ultimately providing an appropriate data package to support the administration of a novel compound to pregnant women. These plans should include validated inclusion criteria and critical risk-reducing steps to avoid exposing patients and their fetuses to novel medications with little chance of efficacy.
Acetylsalicylic acid, for example, is recommended for the prophylaxis of preeclampsia and needs to be initiated using a risk assessment algorithm resulting in a number needed to treat of about 70 pregnant women to benefit only one. This emphasizes the necessity for improved biomarkers for the diagnosis of patients during the asymptomatic phase of the syndromes. Correct patient identification before the onset of symptoms would lower the number needed to treat and reduce the unnecessary exposure of women and fetuses that may be considered at risk based on current criteria but will have normal pregnancy outcomes.
Imperfect Translational Models to Test Novel Therapies
Several natural, genetic, and adapted animal models exist for obstetrical syndromes. However, translational challenges remain as differences in these models compared with humans are evident, including placentation, gestation, parturition, and stage of development at birth. , In the case of preeclampsia, a rodent phenotype with hypertension and proteinuria can be generated through reduced uterine perfusion pressure or by creating transgenic hypertensive animals. These models can be used for the initial testing of drugs to evaluate the improvement of specific disease phenotypes but do only partially replicate the human pathophysiology. The translation of such preclinical results remains a critical issue in R&D strategies toward novel candidates for obstetrical syndromes.
Ideally, a drug for the treatment of maternal or placental disease would not transfer into the fetal blood. The placenta, as a barrier, uses several selective mechanisms to regulate the transfer of molecules, , such as passive diffusion mainly for small molecules (eg, anesthetic drugs, paracetamol, warfarin), or highly specific carrier-mediated transfer and transcytosis for intracellular transport of macromolecules (eg, dexamethasone, digoxin). Drugs can also be metabolized by many different enzymes (eg, cytochrome P450 system) present in the placenta. Establishing whether a compound enters the fetal compartment, and if so to what extent compared with maternal levels, is of critical importance. The human ex vivo placenta perfusion model has been used to predict the transfer of therapeutic drugs but is imperfect as it rapidly loses its physiological function after delivery. Other experimental models of placental transfer have been proposed, including in vivo and ex vivo animal models and in vitro placenta cell culture models, but all models have limitations for extrapolation of results to in vivo human placentas.
Mathematical models to assess changes in the pharmacokinetics of drugs during pregnancy, which combine data from in vitro, ex vivo, and in vivo placental transfer models, have been developed with promising results. However, the prediction of fetal exposure at early gestational ages is particularly challenging because of the paucity of biologic data to fit the model.
Extrapolation of Animal Fetotoxicity Outcomes
Detailed regulatory guidance on the design and timing of nonclinical developmental and reproductive toxicity studies is available for any approved drug targeting women of reproductive age, and outcomes are reported in the drug label. Without observed fetal toxicity in animal studies, labels still require evaluation of the individual benefit risk by prescribers in the absence of safety data in human pregnancy. The recent example of the coronavirus disease 2019 (COVID-19) vaccines for which animal studies “do not indicate direct or indirect harmful effects to reproductive toxicity” is typical. Pregnant women are at risk of severe COVID-19 syndromes, and obstetrics and gynecologic societies, such as the American College of Obstetricians and Gynecologists, recommend that vaccines should not be withheld from pregnant individuals who meet the criteria for vaccination. , Although additional evaluation of COVID-19 vaccines in pregnant women is planned, , vaccines currently available under Emergency Use Authorization (EUA) have not been tested in pregnant women. , Therefore, the EUA Fact Sheet states that data are insufficient to inform vaccine-associated risks in pregnancy and concludes “If you are pregnant or breastfeeding, discuss your options with your healthcare provider.” This statement defers the responsibility for the safety in pregnant women to prescribers. When the detection of a teratogenic or toxic effect in the human fetus is not based on proper clinical trials, it relies on case reports, pharmacovigilance systems, teratogen information services, and registries necessitating substantial postmarketing exposure until causality can be established.
When developing new drugs specifically targeting obstetrical syndromes, all nonclinical female reproduction toxicity studies (covering all stages from premating or conception to postweaning development and growth) must be completed before enrollment of pregnant women to clinical studies. Refinement of nonclinical reproductive toxicity testing strategies has resulted in good concordance between data from rat and rabbit developmental toxicity studies and adverse effects observed in humans. However, because of the uniqueness of human placental, embryologic, and fetal development, the prediction of human teratogenicity from animal reproduction toxicity studies has limitations. Translation of the results does not include long-term developmental consequences. For new molecules specifically targeting obstetrical syndromes, the preclinical reproduction toxicity package may require additional studies, for example, in nonhuman primates with assessment of the placenta transfer level.
Adapting Current Clinical Development Approaches for Obstetrical Syndromes
Major challenges are faced in the design and conduct of clinical trials to ensure maternal, fetal, and long-term infant safety. In standard clinical development, phase I studies assess safety, tolerability, and pharmacokinetics in healthy volunteers; phase II explores efficacy and dose-response in the target population; and phase III confirms efficacy and safety. For obstetrical syndromes, the transition from phase I to phase II or III includes 1 more critical step—from nonpregnant to pregnant women ( Figure 1 ). For drugs to be used exclusively during pregnancy, phase I and II trials should include pregnant women. According to the Food and Drug Association (FDA) guidelines, phase I and II studies in nonpregnant women that include females of reproductive potential should be completed before enrolling pregnant women. If therapeutic options are limited, the benefit-to-risk considerations may favor enrollment of pregnant women in earlier phase trials and hence provide the opportunity to enroll pregnant women with obstetrical syndromes in phase II trials. However, the benefit-to-risk evaluation is impossible at this stage in the absence of fetal exposure assessment and without confirmation of an effective mechanism of action. Furthermore, pharmacokinetic extrapolation from nonpregnant to pregnant women requires specific escalating dose schemes to take into consideration differences in drug absorption, distribution, metabolism, and elimination and increased cardiac output and blood flow changes at the organ level in pregnancy. Physiologically based pharmacokinetic models developed so far to adapt dosing are limited to the evaluation of drugs for use in nonpregnant adults that may be continued during pregnancy. For obstetrical syndromes, such models need to be substantially expanded, integrating animal pharmacokinetic and dose-response data, adding another layer of complexity.
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