Ethics and social acceptability of a proposed clinical trial using maternal gene therapy to treat severe early‐onset fetal growth restriction

Sheppard, Mk; Spencer, Rebecca; Ashcroft, Richard; David, Anna L.

doi:10.1002/uog.15880

Cited by 47 publications

(34 citation statements)

References 19 publications

(20 reference statements)

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“…In stakeholder and patient interviews conducted by the EVERREST consortium, a primary issue raised when considering a trial of maternal gene therapy for FGR, was the additional psychological distress that is added to an already stressful situation, through asking a pregnant woman to consider taking part in a trial (Table 2). Interestingly, maternal gene therapy was for the majority of stakeholders considered to be acceptable if there was clear fetal benefit (76). Likewise, most women felt they had the capacity to make informed decisions whilst pregnant, which aligns with the recommendations by the CIOMS (68), so long as they were provided with the information required to make an autonomous decision.…”

Section: Despite the 2002 Council For International Organizations Of mentioning

confidence: 83%

Placenta-directed gene therapy for fetal growth restriction

Krishnan

David

2017

Seminars in Fetal and Neonatal Medicine

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Fetal growth restriction (FGR) is a serious pregnancy complication affecting ∼8% of all pregnancies. There is no treatment to increase fetal growth in the uterus. Gene therapy presents a promising treatment strategy for FGR, with the use of adenoviral vectors encoding for proteins such as vascular endothelial growth factor (VEGF) and insulin-like growth factor demonstrating improvements in fetal growth, placental function, and neonatal outcome in preclinical studies. Safety assessments suggest no adverse risk to the mother or fetus for VEGF maternal gene therapy; a clinical trial is in development. This review assesses research into placenta-directed gene therapy for FGR, investigating the use of transgenes and vectors, their route of administration in obstetrics, and the steps that will be needed to take this treatment modality into the clinic.

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Section: Despite the 2002 Council For International Organizations Of mentioning

confidence: 83%

Placenta-directed gene therapy for fetal growth restriction

Krishnan

David

2017

Seminars in Fetal and Neonatal Medicine

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“…A bioethical study found no absolute ethical, regulatory, or legal objections to the use of maternal gene therapy in pregnancy, with patients welcoming the development of new drugs for this untreatable disease. 92 The consortium is performing a prospective observational study of pregnancies with severe earlyonset FGR to define their trial inclusion criteria, which is likely to recruit those women who are most at risk of an intrauterine death or neonatal death between 22 and 27 weeks of gestation. 93 Nanotechnology and other uteroplacental targeting strategies to treat FGR There are a number of other novel strategies emerging that could target drugs or particles to the uteroplacental circulation and/or the trophoblast with the aim of improving uterine blood flow, placental function, or both (Table 3).…”

Section: Maternal Vegf Gene Therapymentioning

confidence: 99%

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction

Groom

David

2018

American Journal of Obstetrics and Gynecology

129

101

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Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction co...

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“…There is considerable personal, familial, and societal pressure on pregnant women to act selflessly for their unborn child; she may feel she ‘has no choice’ . When assessing a prenatal therapy, many pregnant women consider their fetus as a baby, even if they have not attained a ‘viable’ gestational age . As fetal intervention moves increasingly into the mainstream, placing safeguards to prevent diminution of maternal autonomy may protect mothers in the long run.…”

Section: The Legal Position On Fetal Interventionmentioning

confidence: 99%

“…46,47 When assessing a prenatal therapy, many pregnant women consider their fetus as a baby, even if they have not attained a 'viable' gestational age. 48 As fetal intervention moves increasingly into the mainstream, placing safeguards to prevent diminution of maternal autonomy may protect mothers in the long run. Furthermore, the fetus's lack of rights prevents its classification as a patient, so it is not supported by the personhood/patienthood structure.…”

Section: The United Kingdommentioning

confidence: 99%

The legal frameworks that govern fetal surgery in the United Kingdom, European Union, and the United States

Cao

Booth

Ourselin³

et al. 2018

Prenatal Diagnosis

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The specialty of fetal surgery or fetal intervention is one of the most exciting emerging fields of modern medicine. It is made possible by decades of major developments in antenatal imaging, obstetric anaesthesia, fetal medicine, paediatric surgery, and of course by the bold and novel practitioners willing to take new steps to advance the field. Beginning in the 1970s, it has now reached a stage of maturity where there are several established in utero procedures and countless clinical trials and studies to develop more. But what is the legal situation that fetal surgeons find themselves in? What are the rights and legal protections for the fetus and the mother, both of which are arguably the patient? This article will address this question, discussing and summarising the current legal frameworks governing fetal surgery in the jurisdictions of the United Kingdom, European Court of Human Rights, and the United States of America as well as discuss what the future may hold and how researchers and physicians in the specialty can best navigate the legal environment.

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Ethics and social acceptability of a proposed clinical trial using maternal gene therapy to treat severe early‐onset fetal growth restriction

Abstract: ABSTRACT

Cited by 47 publications

References 19 publications

Placenta-directed gene therapy for fetal growth restriction

Placenta-directed gene therapy for fetal growth restriction

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction

The legal frameworks that govern fetal surgery in the United Kingdom, European Union, and the United States

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