Sildenafil como tratamiento de la restricción de crecimiento intrauterino, revisión sistemática de la literatura / Sildenafil as a treatment for blood restriction fetal growth, systematic review of the literature

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.

INTRODUCTION AND OBJECTIVE: Intrauterine growth restriction (IUGR) is an insufficient expression of the genetic potential for fetal growth, complicates 5-8% of pregnancies and represents high rates of perinatal morbidity and mortality. Of multifactorial origin, it can be caused by pathologies at the maternal, fetal or placental level. The treatment is limited, opting for a rigorous follow-up with eventual interruption of the pregnancy according to evolution. Different therapeutic strategies have been used for its prevention and management, emerging sildenafil citrate (CS), inhibitor of phosphodiesterase type 5, as a drug that could improve the uteroplacental blood flow and offer better perinatal results in fetuses with IUGR. A review of the available literature on CS as a treatment for IUGR is proposed. METHOD: A search was conducted for literature in English and Spanish. Out of 105 selected articles, 94 were excluded. The information obtained was classified and used as support for this review, following the PRISMA model. RESULTS: We found 11 studies that contrast the use of placebo and CS in patients with IGR. Regarding birth weight gain, only two studies showed significant evidence. Forty cases of fetal/neonatal death associated with CS treatment were reported. CONCLUSIONS: Not enough evidence was found to justify the routine use of CS in IUGR cases. Studies with larger samples and subsequent meta-analysis are still necessary to confirm the benefit of this drug in terms of birth weight gain, prolongation of pregnancy and possible long-term adverse effects.

Sildenafil citrate and uteroplacental perfusion in fetal growth restriction

Background: Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero

Objective: To evaluate effectiveness and safety of Sildenafil citrate for treatment of intrauterine growth restriction [IUGR]

Design: A prospective randomized control study

Setting: At Ain shams University hospital and Kafr Aldwwar main Hospital in El-Beheria governorate

Subjects: Eighty pregnant women with gestational age between 24 and 34 weeks having singleton pregnancy and suffering from IUGR attending an antenatal clinic

Methods: Eighty pregnant women with FGR and abnormal umbilical artery Doppler between 24and34 weeks were randomly allocated to sildenafil [n= 40] 25mg tid or placebo [n=40] with a plenty of fluids until delivery

Main outcome measure: Length of pregnancy, neonatal weight and ICU admission

Results: Sildenafil treatment was associated with a significant increase in length of pregnancy [P> 0.05] and a significant increase in estimated fetal weight by ultrasound [P<0.05], and was associated with a significant decrease in neonatal ICU admission [P=0.218] and neonatal mortality [P=0.290]

Conclusion: Sildenafil citrate can improve utero-placental perfusion and length of pregnancy in pregnancies complicated by IUGR. It appears to have a significantly positive effect on fetal weight. Sildenafil treatment may offer a new opportunity to improve perinatal outcomes, for pregnancies complicated by IUGR. However these observations require further studies on wide scale

L-arginina: suplemento nutricional sin beneficios demostrados en patologías del embarazo / L-arginine supplementation in patients with disorders of pregnancy

Objetivo: análisis crítico de estudios clínicos randomizados para determinar si el suplemento con L-arginina mejora el resultado perinatal en pacientes embarazadas en riesgo o que presenten patologías como parto prematuro, síndrome hipertensivo del embarazo o restricción de crecimiento fetal intrauterino. Métodos: se realizó una búsqueda bibliográfica en base de datos Pubmed, Tripdatabase y una multibúsqueda en el Sistema de Bibliotecas de la Pontificia Universidad Católica de Chile con posterior análisis crítico de los estudios seleccionados. Resultados: se seleccionaron 14 estudios clínicos randomizados; 4 de ellos corresponden a estudios de L-arginina en hipertensión gestacional, 5 estudios de L-arginina en preeclampsia, 1 estudio de L-arginina en parto prematuro, 1 estudio de L-arginina en hipertensión crónica y 4 estudios de L-arginina en restricción de crecimiento intrauterino. Solo dos de los estudios son de buena calidad metodológica, pero uno de ellos estudia un resultado intermedio y no clínicamente relevante. El resultado más promisorio muestra que el uso de L-arginina asociada a vitaminas antioxidantes reduce significativamente la incidencia de preeclampsia en mujeres de riesgo (antecedente personal o familiar de preeclampsia). Conclusiones: no se ha demostrado la efectividad de la suplementación antenatal con L-arginina para mejorar el resultado perinatal en embarazadas en riesgo o que presentan patologías como parto prematuro, síndrome hipertensivo del embarazo o restricción de crecimiento fetal. Se requieren estudios de buen diseño que permitan conclusiones definitivas.

Objective: critical analysis of randomized clinical trials to determine whether supplementation with L-arginine improves perinatal outcome in pregnant patients at risk or presenting conditions such as preterm labor, hypertensive disorders or intrauterine fetal growth restriction. Methods: we performed a literature search in Pubmed, Tripdatabase and multisearch in the Library System of the Pontifical Catholic University of Chile to further critical analysis of selected studies. Results: We selected 14 randomized trials, 4 of them are for studies of L-arginine in gestational hypertension, 5 studies of L-arginine in preeclampsia, one study of L-arginine in preterm labor, one study of L-arginine in chronic hypertension and 4 studies of L-arginine in intrauterine growth restriction. Only two of the studies were of good methodological quality, but one these studies analyzes an intermediate result that is not clinically relevant. The most promising result shows that the use of L-arginine associated with antioxidant vitamins significantly reduced the incidence of preeclampsia in women at risk (personal or family history of preeclampsia). Conclusions: is not shown the effectiveness of antenatal supplementation with L-arginine to improve perinatal outcome in pregnant women at risk or with pathological conditions such as premature labor, hypertensive disorders and fetal growth restriction. More studies of good design are needed to allow definitive conclusions.

Mutações no gene do receptor do fator de crescimento insulina-símile 1 (IGF1R) como causa de retardo do crescimento pré- e pós-natal / Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation

Aproximadamente 10 por cento das crianças nascidas pequenas para a idade gestacional (PIGs) não apresentam recuperação espontânea do crescimento. As causas desse déficit de crescimento pré-natal e sua manutenção após o nascimento ainda não são completamente conhecidas na maioria dos casos. Nos últimos oito anos, diversas mutações inativadoras e deleções do gene IGF1R em heterozigose foram relatadas, indicando o papel de defeitos no eixo IGFs/IGF1R como causa do déficit de crescimento. Postula-se que pelo menos 2,5 por cento das crianças nascidas PIGs possam apresentar defeitos no gene IGF1R. O quadro clínico desses pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento e aos parâmetros hormonais. Nos casos mais evidentes, os pacientes apresentam microcefalia, déficit cognitivo leve e valores elevados de IGF-1, associados à baixa estatura de início pré-natal. Esta revisão abordará os aspectos clínicos, moleculares e do tratamento da baixa estatura com hrGH de crianças com mutações no IGF1R.

Approximately 10 percent of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5 percent of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.

Growth hormone therapy.

Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.

Tratamiento del factor inmunológico en el aborto recurrente y en el retardo de crecimiento intrauterino / Treatment of the immunologic factor in the recurrent abortion and the intrauterine growth retardation

Objetivo: Describir los resultados del tratamiento anti-agregante plaquetario en un grupo de pacientes con auto-anticuerpos y antecedentes de aborto recurrente (AR) y/o retardo de crecimiento intrauterino (RCIU). Material y Método: Catorce pacientes que consultaron por AR y/o RCIU, en cuyo estudio inmunológico se detectaron autoanticuerpos, constituyen el material del presente trabajo. A las pacientes que tenían como antecedentes un RCIU, una vez descartados todos los cuadros clínicos que pudieran ocasionarlo, se les efectuó determinación de autoanticuerpos. Las parejas que consultaban por AR eran sometidas a estudio para descartar un factor uterino, infeccioso, endocrinológico, metabólico, genético, inmunológico y espermático. En algunas pacientes se realizó una laparoscopia para descartar endometriosis. Todas las pacientes fueron tratadas con Acido Acetilsalicílico (AAS) 80 mg. diarios, a partir del momento de la detección de autoanticuerpos. A una sola paciente se le administró además Heparina subcutánea durante dos embarazos. Resultados: De las catorce pacientes en las que se detectaron autoanticuerpos, doce embarazaron, algunas de ellas en más de una oportunidad, sumando un total de 19 embarazos. De ellos, 5 concluyeron en aborto espontáneo y catorce concluyeron en el tercer trimestre con recién nacido vivo. De éstos, cinco presentaron un crecimiento fetal normal, mientras que los nueve restantes desarrollaron RCIU. La vía de terminación fue vaginal en cinco casos y abdominal en los nueve restantes. Conclusiones: El tratamiento del síndrome antifosfolipídico con antiagregantes plaquetarios (AAS o heparina), parecería ofrecer un porvenir reproductivo alentador a las portadoras de dicho síndrome