RESUMO
PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.
Assuntos
Ácido Quenodesoxicólico , Xantomatose Cerebrotendinosa , Humanos , Feminino , Ácido Quenodesoxicólico/uso terapêutico , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genética , Gravidez , Adulto , Colestanotriol 26-Mono-Oxigenase/genética , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/genética , Recém-NascidoRESUMO
OBJECTIVE: This study aimed to evaluate whether implementation of an enhanced recovery after surgery (ERAS) protocol is associated with lower maternal opioid use after cesarean delivery (CD). STUDY DESIGN: We performed a pre- and postimplementation (PRE and POST, respectively) study of an ERAS protocol for cesarean deliveries. ERAS is a multimodal, multidisciplinary perioperative approach. The four pillars of our protocol include education, pain management, nutrition, and early ambulation. Patients were counseled by their outpatient providers and given an educational booklet. Pain management included gabapentin and acetaminophen immediately prior to spinal anesthesia. Postoperatively patients received scheduled acetaminophen and ibuprofen. Oxycodone was initiated as needed 24 hours after spinal analgesia. Preoperative diet consisted of clear carbohydrate drink consumed 2 hours prior to scheduled operative time with advancement as tolerated immediately postoperation. Women with a body mass index (BMI) <40 kg/m2 and scheduled CD were eligible for ERAS. PRE patients were randomly selected from repeat cesarean deliveries (RCDs) at a single site from October 2017 to September 2018, BMI <40 kg/m2, without trial of labor. The POST cohort included women who participated in ERAS from October 2018 to June 2019. PRE and POST demographic and clinical characteristics were compared. Primary outcome was total postoperative morphine milligram equivalents (MMEs). Secondary outcomes included length of stay (LOS) and maximum postoperative day 2 (POD2) pain score. RESULTS: All women in PRE (n = 70) had RCD compared with 66.2% (49/74) in POST. Median total postoperative MMEs were 140.0 (interquartile range [IQR]: 87.5-182.5) in PRE compared with 0.0 (IQR: 0.0-72.5) in POST (p < 0.001). Median LOS in PRE was 4.02 days (IQR: 3.26-4.27) compared with 2.37 days (IQR: 2.21-3.26) in POST (p < 0.001). Mean maximum POD2 pain score was 5.28 (standard deviation [SD] = 1.86) in PRE compared with 4.67 (SD = 1.63) in POST (p = 0.04). CONCLUSION: ERAS protocol was associated with decreased postoperative opioid use, shorter LOS, and decreased pain after CD. KEY POINTS: · ERAS protocol was associated with decreased postoperative opioid use after CD.. · ERAS protocol was associated with shorter length of stay after CD.. · ERAS protocol was associated with decreased postoperative pain after CD..
Assuntos
Analgésicos Opioides/uso terapêutico , Cesárea/reabilitação , Recuperação Pós-Cirúrgica Melhorada/normas , Manejo da Dor/normas , Melhoria de Qualidade , Acetaminofen/uso terapêutico , Adulto , Estudos de Coortes , Feminino , Implementação de Plano de Saúde , Humanos , Ibuprofeno/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Dor Pós-Operatória/tratamento farmacológico , Gravidez , Avaliação de Programas e Projetos de SaúdeRESUMO
Our objective was to determine the role of toll-like receptor 4 (TLR4) in uterine ischemia/reperfusion (I/R)-induced fetal growth restriction (FGR). Pregnant TLR4-deficient and wild-type mice were subjected to I/R or a sham procedure. Fetal and placental weights were recorded and tissues were collected. Pep-1 (inhibits low-molecular-weight hyaluronan (LMW-HA) binding to TLR4) was used to determine whether LMW-HA-TLR4 interaction has a role in FGR. TLR4-deficient mice exhibited significantly lower baseline fetal weights compared with wild-type mice (P<0.05), along with extensive placental calcification that was not present in wild-type mice. Following I/R, fetal and placental weights were significantly reduced in wild-type (P<0.05) but not in TLR4-deficient mice. However, I/R increased fetal loss (P<0.05) only in TLR4-deficient mice. Corresponding with the reduced fetal weights, uterine myeloperoxidase activity increased in wild-type mice (P<0.001), indicating an inflammatory response, which was absent in TLR4-deficient mice. TLR4 was shown to have a regulatory role for two anti-inflammatory cytokines: interferon-B1 decreased only in wild-type mice (P<0.01) and interleukin-10 increased only in TLR4-deficient mice (P<0.001), in response to I/R. Pep-1 completely prevented I/R-induced FGR (P<0.001), indicating a potential role for the endogenous TLR4 ligand LMW-HA in I/R-induced FGR. In conclusion, uterine I/R in pregnancy produces FGR that is dependent on TLR4 and endogenous ligand(s), including breakdown products of HA. In addition, TLR4 may play a role in preventing pregnancy loss after uterine I/R.
Assuntos
Complicações na Gravidez/metabolismo , Traumatismo por Reperfusão/metabolismo , Receptor 4 Toll-Like/metabolismo , Doenças Uterinas/metabolismo , Útero/metabolismo , Animais , Biomarcadores/metabolismo , Calcinose/imunologia , Calcinose/metabolismo , Calcinose/patologia , Calcinose/fisiopatologia , Citocinas/metabolismo , Feminino , Morte Fetal/etiologia , Retardo do Crescimento Fetal/etiologia , Peso Fetal , Ácido Hialurônico/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C3H , Camundongos Mutantes , Proteínas Mutantes/metabolismo , Tamanho do Órgão , Peroxidase/metabolismo , Gravidez , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Complicações na Gravidez/fisiopatologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Receptor 4 Toll-Like/genética , Doenças Uterinas/imunologia , Doenças Uterinas/patologia , Doenças Uterinas/fisiopatologia , Útero/imunologia , Útero/patologiaRESUMO
Fetal growth restriction is most commonly caused by failure of the placenta to meet the increasing demands for oxygen and substrate of the developing fetus, resulting in common fetal compensatory responses. Understanding these responses is helpful in developing a management strategy that will optimize pregnancy outcome.
Assuntos
Retardo do Crescimento Fetal/etiologia , Feto/fisiologia , Placenta/irrigação sanguínea , Insuficiência Placentária/fisiopatologia , Adaptação Fisiológica , Velocidade do Fluxo Sanguíneo , Feminino , Hipóxia Fetal/metabolismo , Hipóxia Fetal/fisiopatologia , Feto/metabolismo , Humanos , GravidezRESUMO
We characterized fetal and placental growth and uterine and placental inflammation in pregnant C3H/HeOuJ and C57BL/6J mice (strains with different sensitivities to metabolic and circulatory pathologies), using different uterine ischemia/reperfusion (I/R) protocols, to establish and refine a murine model of I/R-induced fetal growth restriction (FGR). Pregnant C3H/HeOuJ mice on gestation day 15 were subjected to unilateral uterine I/R by (1) total blood flow restriction (TFR) by occlusion of the right ovarian and uterine arteries for 30 minutes, (2) partial flow restriction (PFR) by occlusion of only the right ovarian artery for 30 minutes, or (3) sham surgery. Pregnant C57BL/6J mice were treated the same, but on gestation day 14 and with TFR for only 5 minutes due to high sensitivity of C57BL/6J mice to I/R. Four days post-I/R, the animals were euthanized to determine fetal and placental weight and fetal loss and to assay placental myeloperoxidase (MPO) activity. In C3H/HeOuJ mice, TFR/30 minutes induced significantly ( P < .05) lower fetal and placental weights and higher placental MPO activity, compared to controls. The PFR/30 minutes produced the same effects except placental weights were not reduced. In contrast, in C57BL/6J mice, TFR for only 5 minutes was sufficient to induce FGR and increase fetal loss; while PFR/30 minutes lowered fetal but not placental weights and increased fetal loss but not placental MPO activity. In summary, we present the first published model of I/R-induced FGR in mice. We find that mice of different strains have differing sensitivities to uterine I/R, therefore differing I/R response mechanisms.
Assuntos
Retardo do Crescimento Fetal/etiologia , Traumatismo por Reperfusão/complicações , Útero/lesões , Animais , Corioamnionite/etiologia , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/metabolismo , Peso Fetal , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Peroxidase/metabolismo , Placenta/metabolismo , Placenta/patologia , Gravidez , Cervicite Uterina/etiologia , Útero/patologiaRESUMO
OBJECTIVE: The objective of the study was to evaluate the role of endothelin-1 and platelet-activating factor in ischemia/reperfusion-induced fetal growth restriction in the rat. STUDY DESIGN: On day 17 of gestation, the right uterine and ovarian arteries were occluded for 30 minutes in experimental but not sham-operated rats. All rats received endothelin receptor A antagonist, A-127722 (10 mg/kg per day), platelet-activating factor antagonist, WEB-2086 (1 mg/kg), or vehicle. On gestational day 21, litter size, fetal viability, and fetal and placental weights were recorded. Reverse transcription-polymerase chain reaction for phospholipase A2-IIA and preproendothelin-1 messenger ribonucleic acid was performed on uterus and placentas from each uterine horn. Groups were compared statistically by analysis of variance. RESULTS: Ischemia/reperfusion reduced fetal weights, in both the ischemic horn and the nonischemic horn (P < .001). Antagonism of either endothelin receptor A or platelet-activating factor normalized fetal growth in both horns. Neither placental weight nor the incidence of fetal demise was affected by ischemia/reperfusion. Phospholipase A2-IIA and preproendothelin-1 messenger ribonucleic acid expression did not differ between right and left uterine horns in any group. Uterine and placental tissues in the ischemia/reperfusion group exhibited increased phospholipase A2-IIA (P < .01) but not preproendothelin-1. CONCLUSION: Endothelin-1 and platelet-activating factor are both important mediators in the pathophysiology of ischemia/reperfusion-induced fetal growth restriction in the rat, contributing to the fetal growth restriction observed in both the ischemic and nonischemic horns. Antagonism of either mediator produces normal fetal growth in this model of fetal growth restriction.
Assuntos
Endotelina-1/metabolismo , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/fisiopatologia , Ovário/irrigação sanguínea , Fator de Ativação de Plaquetas/metabolismo , Traumatismo por Reperfusão/complicações , Útero/irrigação sanguínea , Animais , Antagonistas dos Receptores de Endotelina , Endotelina-1/genética , Feminino , Peso Fetal , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Fosfolipases A/genética , Fosfolipases A/metabolismo , Fosfolipases A2 , Placenta/enzimologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Útero/enzimologiaRESUMO
Fetal growth restriction (FGR) is a common cause of perinatal morbidity and mortality. Suboptimal uteroplacental perfusion is the most commonly identified cause of FGR, and ischemic lesions are often observed in placentas from pregnancies complicated by FGR. Ischemia followed by reperfusion is a strong stimulus to the production of the vasoconstrictor endothelin 1 (ET-1) which has been implicated in several models of FGR. We sought to investigate oxidative stress and placental morphology in a rat model of ischemia-reperfusion (I/R)-induced FGR and to evaluate the role of ET-1 in the observed pathology. Unilateral uterine I/R (30 min) was conducted, with and without simultaneous ET-1 receptor A (ETA) antagonism, on pregnant rats at gestation day 17. Placental tissues collected 24 hours later were evaluated immunohistochemically for oxidative damage. Tissue pathology was studied using quantitative morphometry. Glycogen-rich cellular areas in the placental junctional zone exhibited only 50% intact cells (P < .001) in both uterine horns following unilateral I/R, compared to controls. ETA antagonism prevented damage to the glycogen-rich cellular areas. Oxidative damage in response to I/R was prominent in the labyrinthine layer in both uterine horns and was not affected by ETA antagonism. We conclude that glycogen-rich cellular areas of the placental junctional zone are particularly vulnerable to damage from uterine I/R in the rat. Nucleic acid oxidative damage in the labyrinth is a prominent effect of uterine I/R. ETA antagonism protects placental cellular integrity during I/R challenge but does not prevent nucleic acid oxidative damage.
Assuntos
Antagonistas do Receptor de Endotelina A/administração & dosagem , Retardo do Crescimento Fetal/patologia , Isquemia/patologia , Placenta/efeitos dos fármacos , Placenta/patologia , Pirrolidinas/administração & dosagem , Útero/patologia , Animais , Feminino , Glicogênio/metabolismo , Isquemia/prevenção & controle , Masculino , Ácidos Nucleicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Útero/efeitos dos fármacos , Útero/lesõesRESUMO
Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model. Fetal growth restriction occurred both with NO-deficient conceptuses in the setting of maternal NO production and with maternal NO deficiency in the setting of NO-producing conceptuses. Placental ET-1 expression was increased in NO-deficient dams, ET receptor A (ETA) production increased in endothelial nitric oxide synthase(+/-) placentas, and antagonism of ETA prevented FGR. These results demonstrate that both maternal and conceptus NO deficiency can contribute to FGR and suggest a role for ETA antagonists as therapeutic agents in FGR.
Assuntos
Antagonistas do Receptor de Endotelina A/administração & dosagem , Endotelina-1/metabolismo , Retardo do Crescimento Fetal/metabolismo , Troca Materno-Fetal , Óxido Nítrico Sintase Tipo III/deficiência , Receptor de Endotelina A/metabolismo , Animais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Peso Fetal/efeitos dos fármacos , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/genética , Placenta/efeitos dos fármacos , Placenta/fisiologia , Gravidez , Pirrolidinas/administração & dosagem , RNA Mensageiro/metabolismoRESUMO
OBJECTIVE: Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction. METHODS: Timed-pregnant Sprague-Dawley rats, outfitted with arterial catheters, were maintained in either a normoxic or a normobaric hypoxic (12% oxygen) atmosphere from day 18 to 21 of gestation. During this time, the endothelin receptor A antagonist, A-127722, or its vehicle was administered. Regional blood flow was determined on gestational day 21 using 57Co-labeled microspheres. Data were analyzed by analysis of variance with statistical significance accepted at P<.05. RESULTS: Both placental and uterine placental bed perfusion were significantly decreased by hypoxia and returned to normal values with the endothelin antagonist (P<.01 and P<.05, respectively). Fetal weights were significantly lower in the hypoxic group (P<.001) and restored to control levels by the antagonist. CONCLUSION: In the rat, endothelin contributes little to the regulation of uteroplacental perfusion under normal conditions. Hypoxia results in a decrease in perfusion of the uteroplacental bed and of the placenta, and perfusion in both of these beds is normalized by endothelin A receptor antagonism. We conclude that endothelin plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction by reducing uteroplacental perfusion.
Assuntos
Endotelina-1/fisiologia , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/fisiopatologia , Hipóxia Fetal/complicações , Placenta/irrigação sanguínea , Útero/irrigação sanguínea , Animais , Atrasentana , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Radioisótopos de Cobalto , Antagonistas do Receptor de Endotelina A , Feminino , Feto/irrigação sanguínea , Idade Gestacional , Rim/irrigação sanguínea , Microesferas , Oxigênio/administração & dosagem , Gravidez , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To determine the impact of exogenous platelet-activating factor (PAF) on pregnancy outcome in the rat. METHODS: Carbamyl-PAF (0.05, 0.5, or 5.0 microg/kg per hour) or vehicle was infused intravenously for 7 days by osmotic pump into timed pregnant rats. Infusion was begun on day 14 of a 22-day gestation. Maternal mean arterial blood pressures were measured on days 1, 4, and 7 of the infusion. On gestational day 21 (PAF infusion day 7), fetal and placental weights and viability were evaluated at hysterotomy. Uterine and placental PAF receptor expression was analyzed by reverse transcription-polymerase chain reaction and agarose gel electrophoresis. Data were analyzed by analysis of variance, chi(2), or the Mann-Whitney U test as appropriate. RESULTS: Fetal weights were dose-dependently lower than control, by 19% and 35%, respectively, at dosages of 0.5 and 5.0 microg/kg per hour (P < .001) but were not affected at the 0.05 microg/kg per hour dose of carbamyl-PAF. Placental weights were significantly lower at all doses (P < .001). Fetal demise was dose-dependently higher and was significantly different from the control group at the 0.5 and 5.0 microg/kg per hour doses of carbamyl-PAF (P < .0001). Maternal mean arterial pressures were not altered by these doses of carbamyl-PAF. PAF receptors were expressed abundantly in both uterus and placenta. CONCLUSIONS: Exogenous PAF produces dose-dependent fetal growth restriction in the rat. Placental growth is particularly sensitive to PAF and, coupled with the dose-dependent decline in fetal growth, suggests a dose-dependent decline in function. An elevated level of PAF is detrimental to fetal growth and well-being in the rat.
Assuntos
Retardo do Crescimento Fetal/induzido quimicamente , Fator de Ativação de Plaquetas/administração & dosagem , Receptores Acoplados a Proteínas G , Animais , Pressão Sanguínea , Eletroforese em Gel de Ágar , Feminino , Morte Fetal/induzido quimicamente , Idade Gestacional , Infusões Intravenosas , Tamanho da Ninhada de Vivíparos , Placenta/química , Glicoproteínas da Membrana de Plaquetas/genética , Gravidez , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Útero/químicaAssuntos
Arritmias Cardíacas/diagnóstico , Doenças Fetais/diagnóstico , Monitorização Fetal , Frequência Cardíaca Fetal , Recém-Nascido Prematuro , Cordão Umbilical/anormalidades , Adulto , Diabetes Gestacional/tratamento farmacológico , Feminino , Humanos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Recém-Nascido , National Institute of Child Health and Human Development (U.S.) , Guias de Prática Clínica como Assunto , Gravidez , Estados UnidosRESUMO
The significance of endothelin-1 (ET-1) in platelet-activating factor (PAF)-induced fetal growth restriction (FGR) was evaluated in timed-pregnant rats receiving intravenous carbamyl-PAF (c-PAF; 0.5, 1.0, or 2.5 µg/kg per h) or vehicle, with or without ET-1 receptor A (ET(A)) antagonist (10 or 20 mg/kg per d) for 7 days beginning on gestation day 14. Tissues were collected on day 21. Carbamyl-PAF reduced fetal weights dose dependently. Placental weights were significantly reduced but not dose dependently. ET(A) antagonism prevented FGR at the 0.5, but not the 1.0 and 2.5 µg/kg per h c-PAF doses. Correspondingly, placental, but not uterine, preproET-1 messenger RNA (mRNA) expression (determined by reverse transcription-polymerase chain reaction) was increased at 0.5 µg/kg per h but not at higher c-PAF doses. In summary, c-PAF infusion results in fetal and placental growth restriction in the rat. At low doses of c-PAF, ET-1 is central to the pathophysiology of PAF-induced FGR. At higher c-PAF doses, FGR is induced by mechanisms other than ET-1 action.
Assuntos
Endotelina-1/fisiologia , Retardo do Crescimento Fetal/induzido quimicamente , Fator de Ativação de Plaquetas/administração & dosagem , Animais , Antagonistas do Receptor de Endotelina A , Endotelina-1/genética , Feminino , Peso Fetal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Placenta/anatomia & histologia , Placenta/química , Gravidez , Resultado da Gravidez , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The role of complement in ischemia/reperfusion-induced fetal growth restriction and fetal loss is unknown. C5-deficient or wild type timed-pregnant mice were subjected to unilateral uterine ischemia/reperfusion on gestation day 13, either by (1) partial flow restriction by right ovarian artery clamping for 30 min, or (2) total flow restriction by clamping both ovarian and uterine arteries for 5 min. Ischemia/reperfusion-challenged pregnancy outcomes were compared to sham-operated controls 5 days later. Ischemia/reperfusion-treated wild type mice exhibited significantly increased bilateral fetal loss, which was greater in total flow restriction than in partial flow restriction, and decreased fetal weights, which were the same in total flow restriction and partial flow restriction for the surviving fetuses. Placental weights were unchanged by treatments. Ischemia/reperfusion increased uterine, but not placental, myeloperoxidase activity, which correlated with fetal loss. In contrast, C5-deficient mice were protected from both fetal growth restriction and fetal loss, and exhibited no increase in myeloperoxidase activity. These results demonstrate that unilateral uterine ischemia/reperfusion results in bilateral fetal loss and fetal growth restriction, mediated by a systemic mechanism. In the current model, this pathological process is completely dependent on intact complement component 5.
Assuntos
Complemento C5/imunologia , Morte Fetal/imunologia , Retardo do Crescimento Fetal/imunologia , Placenta/imunologia , Traumatismo por Reperfusão/imunologia , Útero/imunologia , Animais , Complemento C5/genética , Complemento C5/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Morte Fetal/genética , Morte Fetal/metabolismo , Morte Fetal/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Humanos , Camundongos , Camundongos Mutantes , Peroxidase/genética , Peroxidase/imunologia , Peroxidase/metabolismo , Placenta/irrigação sanguínea , Placenta/metabolismo , Placenta/patologia , Gravidez , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Útero/irrigação sanguínea , Útero/metabolismo , Útero/patologiaRESUMO
AIMS: Endothelin receptor A (ET(A)) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ET(A) antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups. MAIN METHODS: Timed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14-21 (term=22 days). The antagonists and their respective doses were ABT-546 (20mg/kg/day) and FR139317 (12 mg/kg/day). On day 21, in six rats per group, maternal and fetal plasma ABT-546 was assayed by HPLC. Five additional rats in each group delivered spontaneously and nursed their pups through postpartum day 7. Viability of newborns, oxygen saturation, litter sizes, and pup weights were recorded on postpartum days 1 and 7. KEY FINDINGS: Fetal antagonist levels reached only 2% of maternal levels (p<0.01). There were no significant differences among groups in length of gestation; litter size; survival, number and weight of live pups at birth and at 7 days postpartum; and tissue oxygen saturation. SIGNIFICANCE: Maternal administration of an ET(A) antagonist, at a dose sufficient to ameliorate FGR, has no adverse impact on survival and growth of neonatal rat pups. ET(A) antagonism, delivered maternally, produces sufficiently low fetal plasma levels of antagonist so as not to present a survival threat to the neonatal pups. The beneficial effects of maternally administered ET(A) antagonism on fetal growth occur in the maternal, not the fetal, compartment.
Assuntos
Azepinas/farmacologia , Antagonistas do Receptor de Endotelina A , Desenvolvimento Fetal/efeitos dos fármacos , Indóis/farmacologia , Pirrolidinas/farmacologia , Animais , Animais Recém-Nascidos , Azepinas/administração & dosagem , Azepinas/farmacocinética , Feminino , Retardo do Crescimento Fetal/prevenção & controle , Indóis/administração & dosagem , Indóis/farmacocinética , Troca Materno-Fetal , Gravidez , Resultado da Gravidez , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To evaluate the pathophysiology of chronic nitric oxide synthase (NOS) inhibition-induced fetal growth restriction (FGR) in the rat. METHODS: Timed-pregnant rats received L-NAME (2.5 mg/kg/h) with or without endothelin (ET-1) receptor A (ETA) antagonist from day 14 to 21 of gestation. In separate groups, ETA antagonist and/or L-NAME were discontinued on day 18. On day 21 fetal and placental weights, and maternal and fetal plasma nitrate/nitrite (NOx) were determined. RESULTS: L-NAME led to FGR, and decreased maternal and fetal NOx. Maternal NOx was further decreased when ETA antagonist was co-administered with L-NAME. ETA antagonism along with L-NAME did not impact fetal growth. Discontinuation of LNAME on day 18 resulted in normal fetal and placental growth at day 21 and an increase of maternal NOx. Simultaneous cessation of both NOS inhibition and ETA antagonism on day 18 produced FGR at day 21, whereas continuation of ETA antagonism after discontinuation of L-NAME resulted in normal fetal growth. CONCLUSIONS: NOS inhibition in the pregnant rat leads to decreased maternal and fetal nitric oxide (NO) production and FGR. The effects of NOS inhibition on fetal growth are reversible, and are mediated at least in part by ET-1. With chronic NOS inhibition, ETA antagonism improves but does not normalize fetal growth, and may allow increased access of L-NAME to the fetal compartment. Continued access of L-NAME to the fetal compartment may limit the effect on fetal growth of any therapeutic intervention in this model of FGR.
Assuntos
Inibidores Enzimáticos/farmacologia , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/fisiopatologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Animais , Feminino , Masculino , Óxido Nítrico , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Endothelin receptor A (ETA) antagonism improves fetal and placental growth and placental perfusion on days 1 and 4, but not day 7 of a 7-day infusion of a nitric oxide synthase (NOS) inhibitor. Our purpose was to evaluate the significance of the degree of ETA antagonist selectivity on uteroplacental perfusion and fetal growth on day 7 of chronic NOS inhibition. METHODS: Timed-pregnant rats were treated with the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg/h) with and without one of the following ETA antagonists or their respective vehicles for 7 days beginning on day 14 of gestation: A-127722 (2,000-fold selective for ETA over ETB), FR139317 (8,000-fold ETA-selective), or ABT-546 (28,000-fold ETA-selective). Uterine and placental perfusion, as well as fetal and placental weight, was evaluated at the 7th day of treatment (gestation day 21). RESULTS: L-NAME administration resulted in a significant reduction in uterine and placental perfusion as well as fetal and placental growth. In the setting of NOS inhibition, ETA antagonism did not improve uterine or placental perfusion or fetal growth after 7 days of infusion irrespective of the degree of selectivity of the antagonist used. CONCLUSIONS: ETA antagonism, irrespective of the degree of receptor selectivity, does not improve fetal growth or uteroplacental perfusion on day 7 of chronic NOS inhibition.
Assuntos
Antagonistas dos Receptores de Endotelina , Retardo do Crescimento Fetal/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Análise de Variância , Animais , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Endotelina/metabolismo , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
The authors evaluate the expression of endothelin-1 (ET-1) and its receptors in the uterus and placenta during maternal nitric oxide synthase (NOS) inhibition. Timed-pregnant rats received L-NAME (2.5 mg/kg/h) or saline from day 14 to 21 of gestation. Uterine and placental tissues collected on day 21 were assayed for preproET-1, ET( A), and ET(B) mRNA expression; localization and expression of ET-1 and receptor proteins; and receptor activity. NOS inhibition did not affect preproET-1 mRNA expression in the placenta or uterus. ET(A) expression decreased in the uterine free wall, but no other changes in receptor mRNA expression were observed in the uterus or placenta. ET-1 and receptor proteins were unchanged. Placental ET(A) and ET(B) receptor binding decreased. Uterine ET(A) receptor binding decreased in the placental bed. ET-1, a prominent mediator during NOS inhibition, is not of uterine or placental origin. Reduced receptor binding activity is the primary means by which these tissues regulate their response to ET-1 in the setting of NOS inhibition.
Assuntos
Endotelina-1/metabolismo , Expressão Gênica , Óxido Nítrico Sintase/antagonistas & inibidores , Placenta/efeitos dos fármacos , Prenhez/metabolismo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Útero/efeitos dos fármacos , Análise de Variância , Animais , Ligação Competitiva , Western Blotting , Endotelina-1/genética , Endotelina-3/metabolismo , Feminino , Imuno-Histoquímica , Radioisótopos do Iodo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/fisiologia , Placenta/anatomia & histologia , Placenta/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Útero/anatomia & histologia , Útero/metabolismoRESUMO
Endothelin 1 (EDN1) plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction in the rat. In this study we evaluated the effects of chronic maternal hypoxia on the expression of endothelin and its receptors and on receptor binding activity in the uterus and placenta of the rat, in order to elucidate their roles in hypoxia-induced fetal growth restriction. Timed-pregnant Sprague-Dawley rats were maintained in either a normoxic or a normobaric hypoxic (12% O(2)) atmosphere from Gestational Days 18-21. Uterine and placental tissues collected on Gestational Day 21 were assayed for Edn1, Ednra, and Ednrb (endothelin receptors) mRNA expression by real-time quantitative RT-PCR, for localization of EDN1 and its receptors by immunohistochemistry, for EDNRA and EDNRB protein expression by Western blot, and for receptor binding activity by homologous competitive binding assays. EDN1 mRNA expression was significantly increased in the hypoxic placenta, but not in the uterus, compared with normoxic controls. Immunohistochemistry revealed increased EDN1 specifically in the labyrinth of the placenta. Receptor mRNA levels were not significantly affected by hypoxia, but EDNRA protein expression was significantly decreased specifically in the uterine placental beds. Receptor binding decreased significantly in response to hypoxia in all tissues investigated, compared with controls. These results suggest that chronic maternal hypoxia results in increased expression of EDN1 in the placenta but not in the uterus, and that reduced binding activity, rather than regulation of receptor expression, is a mechanism by which these tissues regulate the local hemodynamic response to increased endogenous placental EDN1 in the setting of hypoxia.
Assuntos
Endotelina-1/biossíntese , Hipóxia/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Receptor de Endotelina A/biossíntese , Receptor de Endotelina B/biossíntese , Útero/metabolismo , Animais , Ligação Competitiva , Western Blotting , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Gravidez , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: The purpose of this study was to evaluate a strategy for the identification of patients with multiple gestations who are at low risk for preterm delivery. STUDY DESIGN: A prospective observational study among patients with twin and triplet gestations. At 20 and 24 weeks of gestation, screening for bacterial vaginosis and fetal fibronectin was performed, followed by digital and sonographic assessment of the cervix. The treating physicians were blinded to test results. RESULTS: At the 24-week examination, specificities for delivery at >32 weeks of gestation for digital examination (92.9%), fetal fibronectin level (93.9%), cervical length on sonographic scan (85.1%), and combined fetal fibronectin level and cervical length (81.3%) did not differ statistically. Negative predictive values for these tests were >or=95%. All tests performed better at 24 weeks of gestation than at 20 weeks of gestation. CONCLUSION: At 24 weeks of gestation, a normal digital examination, a negative fetal fibronectin level, a normal cervical length on sonographic scan, or the combination of a negative fetal fibronectin level and a normal cervical length each confer a similarly high likelihood of delivery at >32 weeks of gestation in women with multiple gestations.