Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials.

Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct.

Accidental Flibanserin Ingestion in Children Causing Acute Respiratory and Central Nervous System Depression: What Health Care Professionals Need to Know.

This commentary serves to raise awareness for health care professionals about the potential risks of accidental ingestion of flibanserin tablets by children. Flibanserin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women. Since its approval in 2015, the FDA has identified five reports of serious accidental ingestion by toddlers. All five children, boys with ages ranging from 18 months to 2 years, presented with central nervous system and respiratory depression, and two of them required intubation. A combination of hypertension, hyperthermia, and seizure-like activity was also seen in four of the five children. The clinical manifestation resembles serotonin syndrome (eg, tachycardia, hypertension, and muscle stiffness). As flibanserin use increases, greater awareness by health care professionals regarding the risk of accidental pediatric ingestion is needed to facilitate preventative counseling for patients with young children.

Prescription medications for use in pregnancy-perspective from the US Food and Drug Administration.

Obstetrical healthcare providers frequently field questions about the safety of medications recommended or prescribed to their pregnant patients. Most women use as least 1 medication during pregnancy; however, there is little information about the safety or appropriate dosing of many medications during this phase of life. In addition, the development of drugs for use in pregnant women trails behind the development of drugs intended for other sectors of the population. Our goal is to inform the obstetrics community about the US Food and Drug Administration authority and their role in approving drugs for marketing. We begin with the statutes that led to the creation of the Food and Drug Administration and its current organization. We then cover drug development and the Food and Drug Administration review process, including the role of the advisory committee. The different types of drug approvals are discussed, with some specific examples. Finally, we enumerate the drugs specifically approved for use in obstetrics and contrast them with drugs commonly used by pregnant women and drugs used "off-label" during pregnancy. The Food and Drug Administration is committed to protecting and advancing the public health of pregnant women by guiding the development and ensuring the availability of effective and safe therapeutics for obstetrical indications and for medical conditions during pregnancy. We hope this review will inspire more research addressing drug use during pregnancy.

Evidence-based pregnancy testing in clinical trials: Recommendations from a multi-stakeholder development process.

Most clinical trials exclude pregnant women in order to avoid the possibility of adverse embryonic and/or fetal effects. Currently, there are no evidence-based guidelines regarding appropriate methods for identifying early pregnancy among research subjects. This lack of guidance results in wide variation in pregnancy testing plans, leading to the potential for inadequate protection against embryonic or fetal exposure in some cases and unnecessary burdens on research participants in others, as well as inefficiencies caused by disagreements among sponsors, investigators, and regulators. To address this issue, the Clinical Trials Transformation Initiative convened content experts and stakeholders to develop recommendations for pregnancy testing in clinical research based on currently available evidence. Recommendations included: 1) the study protocol should clearly state the rationale for pregnancy testing and the plan for handling positive and indeterminate tests; 2) protocols should include an assessment of the pregnancy testing plan advantages (reduced risk of embryo/fetal exposure) versus the burdens (participant burden, study team workload, costs); 3) protocols should assess the participant burdens regarding the likelihood of false negative and false positive results; 4) participant administered home pregnancy testing should be avoided in clinical trials; and 5) the consent process should describe the extent of knowledge about the study intervention's potential risk to the embryo/fetus and the limitations and consequences of pregnancy testing. CTTI has also developed an online tool to help implement these recommendations.

Domperidone for Lactation: What Health Care Providers Need to Know.

This commentary serves to raise health care provider awareness about the regulatory status and available evidence regarding domperidone for insufficient lactation. Breastfeeding provides significant health benefits for mothers and infants, and insufficient milk production remains the most common reason for early weaning. Domperidone, a dopamine receptor antagonist that may increase milk production, is not approved for any human use in the United States. It is approved in some countries for certain gastrointestinal disorders, but is not approved in any country for lactation enhancement. Domperidone is associated with serious cardiac arrhythmias. The U.S. Food and Drug Administration (FDA) issued an import alert in 2004, updated in 2012, explaining that the importation of domperidone is illegal with limited exceptions, including when imported pursuant to an investigational new drug application. The FDA also issued a public safety warning regarding the use of domperidone for lactation. Nonetheless, domperidone is sometimes being obtained illegally and used in attempts to increase milk production in lactating mothers. There is limited quality evidence for the effectiveness of domperidone for lactation enhancement. In contrast, considerable information exists on domperidone's cardiac risks including QT prolongation, torsades de pointes, and sudden cardiac death, including among lactating women. In light of limited efficacy data that do not offset safety concerns from a public health perspective, we continue to caution against using domperidone for lactation enhancement. Research and drug development are needed to address the significant unmet medical need for lactation disorders.

Retroperitoneal leiomyoma: a case report.

BACKGROUND: Retroperitoneal leiomyomata are rare neoplasms. These masses can be asymptomatic or can cause pelvic discomfort, urinary frequency, abdominal fullness or back pain. CASE: A 28-year-old, nulliparous female presented with worsening dysmenorrhea and bulk symptoms from fibroids. MRI revealed an exophytic anterior lower uterine segment fibroid with internal degeneration. During surgery the fibroid was discovered to be retroperitoneal in location, contrary to preoperative imaging findings. Pathology confirmed a benign leiomyoma. CONCLUSION: The treatment for these masses is complete excision. The retroperitoneal location of this fibroid was not evident on preoperative ultrasound and MRI. Imaging can be used only as a guide for operative planning and does not always represent the anatomy accurately. Surgical excision is required, and only at surgery will the exact anatomical location of the fibroid be ascertained.

Update on trends for inpatient surgical management of tubal ectopic pregnancy in Maryland.

OBJECTIVES: In Maryland, an analysis from 1994-1999 found that most hospitalized patients with tubal pregnancy underwent extirpative operations. The objective of this study was to determine whether practice patterns had changed over time. METHODS: Using the Maryland Health Service Cost Review Commission (HSCRC) database from January 1, 2000-December 31, 2004, subjects were identified by ICD-9 code 633.1, tubal pregnancy. The incidence of hospitalization was estimated based on state census data. Cases were analyzed by demographics, presentation, surgeon volume for ectopics, surgical treatment, length of stay, and charges. RESULTS: There were 2292 cases of tubal pregnancy identified, yielding an incidence for hospitalization of 4.81 per 10,000 women. The mean age of subjects was 29.6. Most were admitted through the emergency department (76.8%). Extirpative procedures were used in 88.01%. ER admission and increasing age were associated with extirpative surgery. Mean length of stay was 1.86 days; mean total charges were $5480.11. CONCLUSIONS: A greater percentage of hospitalized ectopics were treated radically than prior. This may be due to acuity of presentation or regional surgical practices and preferences. Continued surveillance and a move toward improvement of Maryland's outcomes for ectopic pregnancy is needed. We propose an algorithm for emergency triage and management of pregnancy in an unknown location toward this end.

A national analysis of the relationship between hospital volume, academic center status, and surgical outcomes for abdominal hysterectomy done for leiomyoma.

BACKGROUND: Volume-to-outcomes relationships have been established for high-risk surgical procedures. To determine whether hospital volume and academic center status affect surgical outcomes in a lower-risk procedure, morbidity and mortality in patients undergoing abdominal hysterectomy for leiomyoma were evaluated. STUDY DESIGN: Administrative data from the National Inpatient Sample were used to conduct a retrospective analysis of 172,344 individuals who had primary diagnoses of leiomyomata (ICD-9 diagnosis codes of 218.x in the first 2 positions) and who underwent abdominal hysterectomy (ICD-9 procedure codes 68.4 in the first 2 positions) from 1999 to 2003. Comparison was made between teaching hospitals versus nonteaching hospitals and annual case volume in quintiles. Morbidity was considered to be any postoperative condition that is not an expected outcome of hysterectomy and defined as instances in which a patient suffered hemorrhage, ureteral injury, bladder injury, intestinal injury, wound dehiscence, wound infection, deep vein thrombosis, pulmonary embolism, or required blood transfusion. RESULTS: A total of 37 deaths were observed. Mortality was not significantly related to hospital volume or academic medical center status. In contrast, morbidity was found to have a positive association with academic medical center status (odds ratio = 1.34; 95% CI, 1.23 to 1.45), although an inverse relationship between volume and morbidity was observed for extended length of stay (> 3 days) and blood transfusion outcomes in the first 3 (lowest) volume quintiles and for pulmonary embolism in the highest-volume quintile. No important association with volume was found for hemorrhage, ureteral injury, bladder injury, or intestinal injury. CONCLUSIONS: Unlike high-risk procedures, such as esophagectomy, pediatric cardiac surgery, and pancreaticoduodenectomy, mortality for abdominal hysterectomy done for benign indication does not improve with hospital volume or academic center status. The statistically significant positive association between academic medical center status and morbidity merits additional characterization to target areas for improvement.

Prevalence of genital prolapse in 3 ethnic groups.

OBJECTIVE: To compare the prevalence of genital prolapse stratified by Asian American, black and white ethnic groups in women presenting for routine gynecologic examinations and to screen them for symptoms of pelvic floor problems. STUDY DESIGN: This was a descriptive study of women presenting for annual examinations. Demographic information on age, weight, gravidity, parity, weight of largest vaginally delivered infant, gynecologic surgery, medical problems (including hypertension, diabetes, pulmonary disease, smoking) and menopausal status were obtained from the patient and chart. Pelvic organ prolapse was assessed using the quantitative pelvic organ prolapse system. Subjects completed the Pelvic Floor Distress Inventory, which was graded along the 3 scales of Urinary Distress Inventory, Pelvic Organ Prolapse Distress Inventory and Colorectal-Anal Distress Inventory. RESULTS: One hundred sixty-seven women completed the study, including 73 whites, 60 Asian Americans and 34 blacks. The populations differed in that black women had higher body weight and were more likely to smoke, while white patients had lower parity and more use of hormone replacement therapy. Sixty-seven percent of Asian American patients had stage 2 or higher prolapse as compared to 26% of black and 28% of white patients. Multiple logistic regression showed that Asian American ethnicity independently correlated with higher rates of pelvic organ prolapse. There was no difference in survey results by race. CONCLUSION: There may be significant racial differences in the incidence of pelvic floor prolapse, with higher rates of stage 2 prolapse in asymptomatic Asian American women.

Trends for inpatient treatment of tubal pregnancy in Maryland.

OBJECTIVE: The purpose of this study was to determine the burden of tubal pregnancy in Maryland in hospitalized patients and to elicit treatment trends. STUDY DESIGN: Patients who were admitted with tubal pregnancy from January 1, 1994, through March 31, 1999, were identified with the use of the Maryland Health Service Cost Review Commission discharge database. Combining this with census data, we calculated the incidence. Cases were then stratified by demographics, presentation, and surgeon volume. Outcome measures included type of medical treatment,conservative (salpingostomy or salpingotomy) or extirpative operation (salpingectomy, salpingo-oophorectomy, oophorectomy, hysterectomy), length of stay, charges, and disposition. The treatment groups were compared with the use of t tests and linear regression, and associations between demographics and type of operation were analyzed with logistic regression. RESULTS: The database included 3729 cases, which yielded an annual incidence of 5.2 per 10,000 women aged 15 to 45 years. Subjects averaged 29.6 years old and were predominantly African American(52.6%) and white (43.3%). Most of the women (67.8%) were seen in the emergency department and were treated surgically (90.7%). Conservative operation was performed in 18.1% of the women; extirpative operation was performed in 81.9% of the women. Significant predictors for extirpative operation were emergency department admission (odds ratio, 1.44; 95% CI, 1.18-1.75), increasing age (odds ratio, 1.07; 95% CI, 1.06-1.09), African American race (odds ratio, 1.87; 95% CI, 1.51-2.31), higher surgeon volume (odds ratio, 1.28; 95% CI, 1.04-1.57), and market area. Length of stay and total charges were higher for the extirpative group(P <.0001). The study lacked the power to detect differences in outcomes for other nonwhite races (5% power), laparoscopy versus laparotomy (15% power), or operating room charges (14% power). CONCLUSION: These data are limited to hospitalized patients and probably underestimate the true incidence of tubal pregnancy. Most patients underwent extirpative operation. Acuity of presentation and increasing age were appropriate predictors of this group. However, physician volume and black race were also predictors. This may be due to differences in the prevalence of disease, unmeasured clinical factors, patient and physician preferences for treatment, barriers that delayed care, or other socioeconomic factors.