Research with pregnant women: a call to action.

Despite a global need for the use of medication during pregnancy, the medical research community lacks robust evidence for safety and efficacy of treatments and preventives often taken by pregnant women. Given the biological differences between pregnant women and the rest of the population, the need to gather data on the ways in which medications behave in the pregnant body is critical to the health of pregnant women and their offspring. Three ethical reasons are central to this need: 1. Pregnant women deserve access to effective treatment, 2. Pregnant women deserve access to safe treatment, and 3. Pregnant women deserve equitable access to trials carrying the prospect of direct benefit. In this paper, we introduce and frame this Supplement Issue, which presents important conference proceedings of the 2016 Global Forum on Bioethics in Research meeting held in Buenos Aires, Argentina, on the 3rd and 4th of November.

Should Canadian health promoters support a food stamp-style program to address food insecurity?

Food insecurity is an urgent public health problem in Canada, affecting 4 million Canadians in 2012, including 1.15 million children, and associated with significant health concerns. With little political will to address this significant policy issue, it has been suggested that perhaps it is time for Canada to try a food stamp-style program. Such a program could reduce rates of food insecurity and improve the nutritional health of low-income Canadians. In this article, we explore the history of the US food stamp program; the key impetus of which was to support farmers and agricultural interests, not to look after the needs of people living in poverty. Though the US program has moved away from its roots, its history has had a lasting legacy, cementing an understanding of the problem as one of lack of food, not lack of income. While the contemporary food stamp program, now called Supplemental Nutrition Assistance Program (SNAP), reduces rates of poverty and food insecurity, food insecurity rates in the USA are significantly higher than those in Canada, suggesting a food stamp-style program per se will not eliminate the problem of food insecurity. Moreover, a food stamp-style program is inherently paternalistic and would create harm by reducing the autonomy of participants and generating stigma, which in itself has adverse health effects. Consequently, it is ethically problematic for health promoters to advocate for such a program, even if it could improve diet quality.

Is the interleukin 8 promoter polymorphism rs4073/-251T >A associated with Clostridium difficile infection?

The interleukin 8 gene single-nucleotide polymorphism rs4073/-251T >A predisposes to Clostridium difficile infection (CDI), but this association has not been independently validated. In this study, we were unable to replicate this association in either a white cohort or by meta-analysis, suggesting that rs4073/-251T >A is unlikely to constitute a major risk factor for CDI.

Serum mannose-binding lectin concentration, but not genotype, is associated with Clostridium difficile infection recurrence: a prospective cohort study.

BACKGROUND: Mannose-binding lectin (MBL) plays a key role in the activation of the lectin-complement pathway of innate immunity, and its deficiency has been linked with several acute infections. However, its role in predisposing to, or modulating disease severity in, Clostridium difficile infection (CDI) has not been investigated. METHODS: We prospectively recruited 308 CDI case patients and 145 control patients with antibiotic-associated diarrhea (AAD). CDI outcome measures were disease severity, duration of symptoms, 30-day mortality, and 90-day recurrence. Serum concentrations of MBL were determined using a commercial enzyme-linked immunosorbent assay transferred to an electrochemiluminescence-based platform. MBL2 polymorphisms were typed using a combination of pyrosequencing and TaqMan genotyping assays. RESULTS: The frequency of the MBL2 genetic variants was similar to that reported in other white populations. MBL serum concentrations in CDI and AAD subjects were determined by MBL2 exonic variants B, C, and D and the haplotypes (LYPB, LYQC, and HYPD). There was no difference in either MBL concentrations or genotypes between cases and controls. MBL concentration, but not genotype, was a determinant of CDI recurrence (odds ratios, 3.18 [95% confidence interval {CI}, 1.40-7.24] and 2.61 [95% CI, 1.35-5.04] at the <50 ng/mL and <100 ng/mL cutoff points, respectively; P < .001). However, neither MBL concentration nor MBL2 genotype was linked with the other CDI outcomes. CONCLUSIONS: Serum MBL concentration did not differentiate between CDI cases and AAD controls, but among CDI cases, MBL concentration, but not genotype, was associated with CDI recurrence, indicating that MBL acts as a modulator of disease, rather than a predisposing factor.

Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin.

Mutations in the perforin gene (PRF1) are a common cause of the fatal immune dysregulation disorder, familial hemophagocytic lymphohistiocytosis (type 2 FHL, FHL2). Here we report a female infant born with biallelic PRF1 mutations: a novel substitution, D49N, and a previously identified in-frame deletion, K285del. We assessed the effects of each mutation on the cytotoxicity of human NK cells in which the expression of endogenous perforin was ablated with miR30-based short hairpin (sh) RNAs. Both mutations were detrimental for function, thereby explaining the clinically severe presentation and rapidly fatal outcome. We demonstrate that D49N exerts its deleterious effect by generating an additional (third) N-linked glycosylation site, resulting in protein misfolding and degradation in the killer cell. Our data provide a rationale for treating some cases of type 2 familial hemophagocytic lymphohistiocytosis, based on the pharmacologic inhibition or modification of glycosylation.

Midwifery support in labour: how important is it to stay in the room?

This paper draws on the findings of an observational study of intrapartum care in Scotland, UK. Observations lasting up to three hours were undertaken of 49 labour episodes. Quantitative data gathered through the study identified associations between women's feelings about the support they received and the proportion of time that their midwife was present in the labour room and between the midwife's presence and the type of birth. Reflections on the care observed during the 104 hours of observations identified several key consequences of the midwife's absence from the room: heightened anxiety of the woman and her birth partner; a reduction in opportunities to build rapport and offer support; and a reduction in the midwife's ability to monitor the progress of the labour accurately. The study also found that those midwives who were out of the room more, were less supportive of the women in their care when they were in the room.

IRB Decision-Making about Minimal Risk Research with Pregnant Participants.

Pregnant individuals are often excluded from research without clear justification, even when the research poses minimal risk of harm to the fetus. Little is known about institutional review board (IRB) decision-making practices when reviewing such research. We conducted a survey of current and former IRB personnel in the United States to elicit their interpretations of "minimal risk"-a formal regulatory category-and to identify factors that may influence IRB decisions to approve or disapprove research involving pregnant participants. Study results revealed some consensus among IRB members about the risk level of individual research procedures and hypothetical study vignettes. However, we uncovered important variations not only in the assessment of risk but also in the willingness of IRB members to approve minimal risk research that includes pregnant women. Based on our findings, guidance is needed to assist IRB members in characterizing risk, applying federal regulations, and appropriately ensuring the inclusion or justified exclusion of pregnant people in research.

Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response.

Zika virus, influenza, and Ebola have called attention to the ways in which infectious disease outbreaks can severely - and at times uniquely - affect the health interests of pregnant women and their offspring. These examples also highlight the critical need to proactively consider pregnant women and their offspring in vaccine research and response efforts to combat emerging and re-emerging infectious diseases. Historically, pregnant women and their offspring have been largely excluded from research agendas and investment strategies for vaccines against epidemic threats, which in turn can lead to exclusion from future vaccine campaigns amidst outbreaks. This state of affairs is profoundly unjust to pregnant women and their offspring, and deeply problematic from the standpoint of public health. To ensure that the needs of pregnant women and their offspring are fairly addressed, new approaches to public health preparedness, vaccine research and development, and vaccine delivery are required. This Guidance offers 22 concrete recommendations that provide a roadmap for the ethically responsible, socially just, and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens. The Guidance was developed by the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group - a multidisciplinary, international team of 17 experts specializing in bioethics, maternal immunization, maternal-fetal medicine, obstetrics, pediatrics, philosophy, public health, and vaccine research and policy - in consultation with a variety of external experts and stakeholders.

The National Children's Study: a golden opportunity to advance the health of pregnant women.

With a $3 billion investment by the federal government, the National Children's Study (NCS) recently began recruitment. The NCS is a golden-and potentially missed-opportunity to study one of the most underrepresented populations in clinical research: pregnant women. As the nation's largest-ever study of children's health, the NCS will examine the effects of the environment on children from before birth to 21 years of age, with participants sampled primarily through women during pregnancy. Thus the NCS presents a rare opportunity to study the health of women during and after pregnancy, in addition to the health of their children. On both moral and policy grounds, we make the case for inclusion of women's health outcomes in the NCS.

Acquired tracheoesophageal fistula during treatment for pediatric acute lymphoblastic leukemia.

Management of pediatric malignancy can result in disruption of the integrity of the gastrointestinal mucosa through a variety of mechanisms. We describe a pediatric oncology patient who developed a tracheoesophageal fistula as a complication of treatment for acute lymphoblastic leukemia.

Finding autonomy in birth.

Over the last several years, as cesarean deliveries have grown increasingly common, there has been a great deal of public and professional interest in the phenomenon of women 'choosing' to deliver by cesarean section in the absence of any specific medical indication. The issue has sparked intense conversation, as it raises questions about the nature of autonomy in birth. Whereas mainstream bioethical discourse is used to associating autonomy with having a large array of choices, this conception of autonomy does not seem adequate to capture concerns and intuitions that have a strong grip outside this discourse. An empirical and conceptual exploration of how delivery decisions ought to be negotiated must be guided by a rich understanding of women's agency and its placement within a complicated set of cultural meanings and pressures surrounding birth. It is too early to be 'for' or 'against' women's access to cesarean delivery in the absence of traditional medical indications--and indeed, a simple pro- or con- position is never going to do justice to the subtlety of the issue. The right question is not whether women ought to be allowed to choose their delivery approach but, rather, taking the value of women's autonomy in decision-making around birth as a given, what sorts of guidelines, practices, and social conditions will best promote and protect women's full inclusion in a safe and positive birth process.

Risk and the pregnant body.

Reasoning well about risk is most challenging when a woman is pregnant, for patient and doctor alike. During pregnancy, we tend to note the risks of medical interventions without adequately noting those of failing to intervene, yet when it's time to give birth, interventions are seldom questioned, even when they don't work. Meanwhile, outside the clinic, advice given to pregnant women on how to stay healthy in everyday life can seem capricious and overly cautious. This kind of reasoning reflects fear, not evidence.

Beyond "Vessels and Vectors": A Global Review of Registered HIV-Related Clinical Trials with Pregnant Women.

BACKGROUND: Since the early 1990s, the HIV research agenda has prioritized to some degree the inclusion of pregnant women. However, concerns remain regarding the extent to which pregnant women's own health needs are addressed, representation in trials of HIV preventives or treatments for comorbidities, and equitable study of newer medications during pregnancy. METHODS: We employed a keyword search of the International Clinical Trials Registry Platform to identify interventional HIV-related trials conducted with pregnant women between January 2001 and December 2015. Retained trials were coded according to several key variables (e.g., study endpoints, trial phase, study compound) and analyzed using information provided in the database. RESULTS: In total, 63 trials studying use of a pharmacological compound during pregnancy were conducted across 35 countries and sponsored by 74 unique organizations, including pharmaceutical companies. Of trials analyzed, 86% (n = 54) listed maternal outcomes as a primary endpoint. More than 35% (n = 23) of trials assessed pharmacokinetic parameters of a study compound during pregnancy. Of 45 trials specifically studying HIV-related medication(s), just 4% (n = 2) focused on HIV preventives. One trial studied tuberculosis in HIV-infected pregnant women; 11 studied malaria. On average, medications were studied during pregnancy 4.4 years after licensure. CONCLUSIONS: Our findings demonstrate that trials with pregnant women are conducted across a range of countries and sponsors, and much progress has been made to better address pregnant women's own health needs in HIV research. However, our findings confirm other concerns, for example, lack of HIV preventives studied and the lag between medication licensure and study during pregnancy.

Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis.

The Anaphase Promoting Complex (APC) coactivator Cdh1 drives proper cell cycle progression and is implicated in the suppression of tumorigenesis. However, it remains elusive how Cdh1 restrains cancer progression and how tumor cells escape the inhibition of Cdh1. Here we report that Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner. Depleting Cdh1 accelerates breast cancer cell proliferation and cooperates with PTEN loss to promote breast tumor progression in mice. Hyperactive c-Src, on the other hand, reciprocally inhibits the ubiquitin E3 ligase activity of APCCdh1 through direct phosphorylation of Cdh1 at its N-terminus, which disrupts the interaction between Cdh1 and the APC core complex. Furthermore, pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function to repress a panel of APCCdh1 oncogenic substrates. Our findings reveal a reciprocal feedback circuit of Cdh1 and c-Src in the crosstalk between the cell cycle machinery and the c-Src signaling pathway.

Women's views about contraception requirements for biomedical research participation.

The scientific and ethical importance of including women of reproductive age in biomedical research is widely acknowledged. Concerns about preventing fetal exposure to research interventions have motivated requirements for contraception among reproductive aged women in biomedical studies-often irrespective of risks and benefits or a woman's actual potential for pregnancy, raising important questions about when such requirements are appropriate. The perspectives of women themselves on these issues are largely unexplored. We conducted 140 interviews, 70 in the U.S. and 70 in Malawi, with women either living with or at-risk for HIV, exploring their views about the practice of requiring contraception in clinical trials. A majority of women interviewed from both countries indicated overall support for the practice, with seven themes characterizing advantages and disadvantages raised: reproductive control, health effects, prevention of fetal harm, burden on women, deferral to authority, autonomy regarding enrollment and birth control method, and relationship concerns. While women in the US frequently raised prevention of fetal harm as a key advantage, many other positives noted by women in both countries were related to contraception use in general, not specific to a trial context. With regard to disadvantages, U.S. women tended to focus on biomedical risks such as side effects and impact on fertility, whereas Malawian women focused on the social risks of contraception requirements, including violations of trust in marital relations and suspicions of potential infidelity. Given the potential benefits and burdens highlighted, contraception in research should be sensitive to actual fetal risk assessments; directed where justified at optimizing effective pregnancy prevention; responsive to women's reproductive preferences; and made available as an ancillary benefit even where risk thresholds do not justify requirement-in order to facilitate trials that are both ethical and robustly oriented around the interests and lives of women who will participate in them.

Mode of delivery: toward responsible inclusion of patient preferences.

Deciding when and how to incorporate patient preferences regarding mode of delivery is challenging for both obstetric providers and policymakers. An analysis of current guidelines in four clinical scenarios (prior cesarean, twin delivery, breech presentation, and maternal request for cesarean) indicates that some guidelines are highly prescriptive whereas others are more flexible, based on physicians' discretion or (less frequently) patient preferences, without consistency or explicit rationale for when such flexibility is permissible, advisable, or obligatory. Although patient-choice advocates have called for more patient-responsive guidelines, concerns also have been raised, especially in the context of discussions of cesarean delivery on maternal request, about the dangers of unfettered patient-preference-driven clinical decisions. In this article, we outline a framework for the responsible inclusion of patient preferences into decision making regarding approach to delivery. We conclude, using this framework, that more explicit incorporation of patient preferences is called for in the first three scenarios and indicate why expanding access to cesarean delivery on maternal request is more complicated and would require more data and further consideration.

Risks, values, and decision making surrounding pregnancy.

Assessing, communicating, and managing risk are among the most challenging tasks in the practice of medicine and are particularly difficult in the context of pregnancy. We analyze common scenarios in medical decision making around pregnancy, from reproductive health policy and clinical care to research protections. We describe three tendencies in these scenarios: 1) to consider the probabilities of undesirable outcomes alone, in isolation from women's values and social contexts, as determinative of individual clinical decisions and health policy; 2) to regard any risk to the fetus, including incremental risks that would in other contexts be regarded as acceptable, as trumping considerations that may be substantially more important to the wellbeing of the pregnant woman; and 3) to focus on the risks associated with undertaking medical interventions during pregnancy to the exclusion of demonstrable risks to both woman and fetus of failing to intervene. These tendencies in the perception, communication, and management of risk can lead to care that is neither evidence-based nor patient-centered, often to the detriment of both women and infants.

Research with Pregnant Women: New Insights on Legal Decision-Making.

U.S. researchers and scholars often point to two legal factors as significant obstacles to the inclusion of pregnant women in clinical research: the Department of Health and Human Services' regulatory limitations specific to pregnant women's research participation and the fear of liability for potential harm to children born following a pregnant woman's research participation. This article offers a more nuanced view of the potential legal complexities that can impede research with pregnant women than has previously been reflected in the literature. It reveals new insights into the role of legal professionals throughout the research pathway, from product conception to market, and it highlights a variety of legal factors influencing decision-making that may slow or halt research involving pregnant women. Our conclusion is that closing the evidence gap created by the underrepresentation and exclusion of pregnant women in research will require targeted attention to the role of legal professionals and the legal factors that influence their decisions.

Videophone support for an eight-year-old boy undergoing paediatric bone marrow transplantation.

We report the use of an Internet-based videophone to support a child undergoing bone marrow transplantation (BMT). Over the Christmas period, an eight-year-old boy with an underlying diagnosis of attention-deficit/hyperactivity disorder (ADHD) and a history of absconding and aggressive non-compliant behaviour was treated by BMT. We installed an Internet-based videophone in the patient's hospital room two days post-transplant. A second videophone was installed in the patient's home and used the existing home telephone line. In all, 14 videophone calls were made over a nine-day period. The videophone improved interfamily social and emotional support, and appeared to reduce some of the inherent anxiety and distress resulting from paediatric bone marrow transplantation.