Perinatal deaths after sildenafil treatment of fetal growth restriction raise the issue of safety in randomised clinical trials

Lombardi, Niccolò; Crescioli, Giada; Bettiol, Alessandra; Ravaldi, Claudia

doi:10.1002/pds.4740

Cited by 8 publications

(9 citation statements)

References 10 publications

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“…The suggested mechanism of toxicity is sudden cessation of the vasodilator agent, which is known as a type E (end-of-use or withdrawal) adverse drug reaction. This implies that sudden cessation of the drug carries an unpredictable risk of rapid deterioration [ 27 ].…”

Section: Reviewmentioning

confidence: 99%

A Systematic Review of Sildenafil Mortality Through the Years

Ibrahim¹,

Ghallab²,

Alhumaid³

et al. 2022

Cureus

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Sildenafil is a medication used for the treatment of erectile dysfunction. It was approved by the U.S. Food and Drug Administration (FDA) in 1998. Several articles have raised concerns regarding the use of sildenafil and the occurrence of serious adverse events, such as myocardial ischemia, stroke, and even death. Our aim is to systematically review the existing literature on mortality associated with sildenafil use. The method used for this systematic review was completed by searching three databases: PubMed, Scopus, and Web of Science. Articles were screened and assessed for eligibility. This review uses the articles found to address the concerns associated with sildenafil and mortality. A total of 19 reports were used in our systematic review, in which there were 10 case reports, two case series, three systematic reviews, one narrative review, one retrospective study, one article in the British Medical Journal , and one commentary article. One FDA article in particular included case reports and reports to the FDA on the use of sildenafil eight months after its introduction to the market in 1998, with 522 deaths reported. Another retrospective study examined the use of sildenafil on infants below the age of 1 who did not have congenital heart disease but did suffer from severe pulmonary hypertension. The study found a mortality rate of 29%, which increased with sildenafil dosage. A case series examined six deaths related to non-prescription use of sildenafil. All these cases were subjected to autopsies and related to sexual activity. The study suggests that phosphodiesterase 5 inhibitors induced the deaths, and the concentration of sildenafil in the femoral blood was found to be between 0.032and0.087 μg. To conclude, the literature available on this topic is deemed insufficient to provide enough data to establish a direct link of causality between sildenafil and mortality. Although some studies paint sildenafil as the culprit behind these deaths, further studies and research are needed to explain the unexpected deaths following sildenafil use.

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Section: Reviewmentioning

confidence: 99%

A Systematic Review of Sildenafil Mortality Through the Years

Ibrahim¹,

Ghallab²,

Alhumaid³

et al. 2022

Cureus

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“…En relación con el estudio realizado en Holanda, este no logró completarse debido a sus resultados preliminares. En el grupo tratado con sildenafil, 17 recién nacidos desarrollaron hipertensión pulmonar, de los cuales 11 fallecieron 26 , mientras que en el grupo con placebo tres recién nacidos presentaron la patología sin producirse ninguna muerte neonatal. Dado lo anterior, surge una alarma en el grupo STRIDER y se suspende el estudio en curso.…”

Section: Discussionunclassified

Sildenafil como tratamiento de la restricción de crecimiento intrauterino, revisión sistemática de la literatura

Klaassen-Campos¹,

Valenzuela-Dechent²,

Sáez-Correa³

et al. 2024

RECHOG

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Introducción y objetivo: La restricción del crecimiento intrauterino (RCIU), expresión insuficiente del potencial genético de crecimiento fetal, complica el 5-8% de los embarazos, con unas altas tasas de morbimortalidad perinatal. De origen multifactorial, puede ser causada por patologías maternas, fetales o placentarias. El tratamiento es limitado, optándose por un seguimiento riguroso con eventual interrupción del embarazo según la evolución. Se han utilizado diferentes estrategias terapéuticas para su prevención y manejo, surgiendo el citrato de sildenafil (CS), inhibidor de la fosfodiesterasa tipo 5, como fármaco que podría mejorar el flujo sanguíneo uteroplacentario y ofrecer mejores resultados perinatales en fetos con RCIU. Se propone realizar una revisión de la literatura disponible en relación al CS como tratamiento del RCIU. Método: Se realizó una búsqueda de literatura en inglés y español. De 105 artículos seleccionados, se excluyeron 94. La información obtenida fue clasificada y utilizada como soporte para la realización de esta revisión, siguiendo el modelo PRISMA. Resultados: Se encontraron 11 estudios que contrastan el uso de placebo y CS en pacientes con RCIU. Respecto al aumento de peso al nacimiento, solo dos estudios demostraron evidencia significativa. Se reportaron 40 casos de muerte fetal/ neonatal asociada al tratamiento con CS. Conclusiones: No se encontró evidencia suficiente que justifique el uso sistemático de CS en casos de RCIU. Aún es necesario realizar estudios con muestras de mayor tamaño y posterior metaanálisis para confirmar el beneficio farmacológico en cuanto al aumento de peso de nacimiento, la prolongación del embarazo y los posibles efectos adversos a largo plazo.

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“…The findings and the halting of the STRIDER trials were widely covered by public media. They sparked an academic polemic about the potential pathophysiologic etiology of the findings [ 83 , 84 , 85 ], the robustness of supporting preclinical data [ 86 ], and the fallout on other indications for which antenatal sildenafil was considered [ 87 , 88 ]. The trial’s authors recently reported in more detail on the patients with pulmonary hypertension (PH) and deceased neonates, describing a higher incidence of early PH in sildenafil-exposed cases, yet without difference in late-onset PH or PH-related mortality [ 89 ].…”

Section: Fetal Growth Restrictionmentioning

confidence: 99%

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

Bie

Basurto

Kumar

et al. 2022

IJERPH

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Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

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Perinatal deaths after sildenafil treatment of fetal growth restriction raise the issue of safety in randomised clinical trials

Cited by 8 publications

References 10 publications

A Systematic Review of Sildenafil Mortality Through the Years

A Systematic Review of Sildenafil Mortality Through the Years

Sildenafil como tratamiento de la restricción de crecimiento intrauterino, revisión sistemática de la literatura

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

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