Safety and effectiveness of the reduction or withdrawal of antihypertensive therapy in pregnant women with chronic hypertensive vascular disease

ilustraciones, gráficas, tablasObjective: To estimate the security and effectivity of the reduction or retirement of antihypertensive medication in pregnant women with chronic hypertension. Methods: Randomized controlled trials that compared management with antihypertensive drugs vs. no antihypertensive, discontinuation of the drug, placebo, or other interventions were included. We searched CENTRAL, MEDLINE, LILACS, and ClinicalTrials. We also hand-searched conference proceedings (ACOG, FIGO, RCOG, FECOLSOG) and reference lists of retrieved studies. Two review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We resolved disagreements through consensus. We used the GRADE approach to assess the quality of evidence. Results: The search did not find any controlled clinical trial evaluating the reduction or withdrawal of antihypertensive therapy. When antihypertensive management was compared with placebo or no antihypertensive, we found that antihypertensive treatment was associated with reduction of probability of developing severe hypertension in pregnant women with chronic hypertension (OR 0,43 95% CI 0.26 to 0.70 ) and increased probability of adverse effects associated to antihypertensive management (aOR 8.52; 95% CI 1.05 to 69). We did not found differences in the probability of developing superimposed pre-eclampsia, preterm birth, placental abruption, small for gestational age, pregnancy loss, neonatal death, admission to the neonatal intensive care unit or low APGAR at birth. We did not found differences in gestational age at birth. Quality of the evidence was very low due to the presence of serious risk of bias, limitations in the applicability of results and the confidence interval. Conclusion: Very low-quality evidence suggest that probably antihypertensive therapy reduces the incidence of severe hypertension in pregnant women with chronic hypertension when compared with placebo or no antihypertensive.Objetivo: Estimar la seguridad y efectividad de la reducción o retiro de la medicación antihipertensiva en mujeres embarazadas con hipertensión crónica. Métodos: Se incluyeron ensayos controlados aleatorios que compararon el tratamiento con fármacos antihipertensivos versus ningún antihipertensivo, suspensión del fármaco, placebo u otras intervenciones. Se realizaron búsquedas en CENTRAL, MEDLINE, LILACS y ClinicalTrials. También se realizaron búsquedas manuales en las actas de congresos (ACOG, FIGO, RCOG, FECOLSOG). Dos autores de la revisión evaluaron de forma independiente los ensayos para su inclusión, extrajeron los datos y evaluaron el riesgo de sesgo. Los desacuerdos fueron resultos por consenso. Utilizamos el enfoque GRADE para evaluar la calidad de la evidencia. Resultados: La búsqueda no encontró ningún ensayo clínico controlado que evaluara la reducción o el retiro de la terapia antihipertensiva. Cuando se comparó el tratamiento antihipertensivo con placebo o ningún antihipertensivo, encontramos que el tratamiento antihipertensivo se asoció con una reducción de la probabilidad de desarrollar hipertensión grave en mujeres embarazadas con hipertensión crónica (OR 0,43; IC del 95%: 0,26 a 0,70) y una mayor probabilidad de efectos adversos. asociado al tratamiento antihipertensivo (ORa 8,52; IC del 95%: 1,05 a 69). No encontramos diferencias en la probabilidad de desarrollar preeclampsia superpuesta, parto prematuro, desprendimiento de placenta, pequeño para la edad gestacional, pérdida del embarazo, muerte neonatal, ingreso en la unidad de cuidados intensivos neonatales o APGAR bajo al nacer. No encontramos diferencias en la edad gestacional al nacer. La calidad de la evidencia fue muy baja debido a la presencia de un riesgo grave de sesgo, las limitaciones en la aplicabilidad de los resultados y el intervalo de confianza. Conclusión: La evidencia de muy baja calidad sugiere que probablemente la terapia antihipertensiva reduce la incidencia de hipertensión severa en mujeres embarazadas con hipertensión crónica en comparación con placebo o ningún antihipertensivo. (Texto tomado de la fuente).Texto en inglésRevisión sistemática con meta-análisisEspecialidades MédicasEspecialista en Obstetricia y GinecologíaMethods Criteria for including studies in this review Randomized controlled trials or non-randomized controlled trials, published, unpublished and ongoing. Types of participants Pregnant women with a diagnosis of chronic hypertensive vascular disease defined as: systolic blood pressure greater than 130 mm Hg or diastolic pressure greater than 80 mm Hg (2,3) on at least two occasions 4 hours apart, before pregnancy or before 20 weeks of pregnancy (4). Type of intervention Withdrawal of antihypertensive drugs defined as abrupt suspension of drug use, de-staging of the drug until the withdrawal is complete, or decrease in current drug dose (16); versus: 1. Continue usual antihypertensive therapy with one or more medications of the type: alpha 2 agonists, calcium antagonists, alpha and beta blockers, alpha adrenergic antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, vasodilators, and diuretics. 2. Placebo. 3. Other interventions. Types of outcomes Primary Outcomes Maternal: Maternal death: Defined as the death of a woman due to direct or indirect obstetric causes during pregnancy or up to 42 days after its termination, regardless of the place in which it occurred or its duration (31). Severe preeclampsia: Defined as finding after week 20 of gestation up to 6 weeks postpartum of systolic blood pressure values greater than or equal to 160 mm Hg or diastolic blood pressure values greater than or equal to 110 mm Hg on two occasions separated by a short interval of time (5-15 minutes), or the finding of systolic blood pressure values greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg on at least two occasions separated by four hours and associated with: thrombocytopenia (platelet count less than 100 x 109 / L); impaired liver function indicated by abnormal serum levels of liver enzymes (twice the higher level of reference); persistent severe pain in epigastrium or right upper quadrant not due to other diagnoses; renal failure (serum creatinine greater than 1.1 mg / dL or twice the baseline serum creatinine concentration in the absence of other kidney disease); pulmonary edema; recent-onset headache that does not respond to analgesic management and is not related to alternative diagnoses; hyperreflexia; visual disturbances such as photophobia, blurred vision, photopsia, scotomas, or blindness that are not related to alternative diagnoses (32); eclampsia defined as the sudden onset of focal or multifocal tonic-clonic seizures in the absence of other conditions that cause it such as epilepsy, cerebral ischemia or infarction, intracranial hemorrhage or use of medications; or HELLP syndrome defined as elevated lactic acid dehydrogenase (LDH) greater than or equal to 600 IU / L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than twice the upper limit of normality and platelets less than 100 x 109 / L (4). Admission to the Intensive Care Unit: defined as the requirement for care in intermediate or intensive care units (33). Adverse reactions: defined as adverse events caused by the withdrawal or use of antihypertensive medications, including palpitations, headache, joint pain, lower limb edema, orthostatic hypotension or rebound hypertension, in addition to changes in serum biochemistry, heart rate, pulse rate, kidney function, and left ventricular parameters (34). Fetal: Loss of pregnancy: Defined as abortion (death of the fruit of conception before week 20 or less than 500 g) or death (death of a fetus in utero after week 20 and greater than 500 g) (26). Neonatal Mortality: defined as those newborns who die before reaching 28 days of life (35). APGAR less than or equal to 5 at minute 5: defined by the Apgar scale that assesses the viability of a newborn according to five simple physio-anatomical parameters: muscle tone, respiratory effort, heart rate, reflexes and skin color, each parameter is assigned a score between 0 and 2 (36). Neonatal intensive care unit admission: defined as admission of a neonate to a neonatal intensive care unit for some neonatal condition that requires surveillance or monitoring (37). Among the causes of admission are: prematurity or birth weight less than 1500 g, gestational age less than 32 weeks, respiratory distress that requires ventilatory support (continuous positive pressure in the airway, mechanical ventilation), seizure syndrome; congenital abnormalities or inborn errors of metabolism, congenital heart disease or cardiac arrhythmias requiring cardiac management, hypoxic-ischemic encephalopathy, other conditions requiring neonatological consultation (severe hyperbilirubinemia, severe intrauterine growth restriction, birth weight between 1000 g 2000 g and gestational age between 32 and 36 weeks (38). Secondary outcomes Maternal Severe arterial hypertension: Defined as the finding of systolic blood pressure values greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 110 mm Hg on two occasions separated by a short time interval (minutes) (4). Gestational age at delivery: Defined as weeks from conception to the date of delivery. It will be calculated taking into account the gestational age reported in the first trimester ultrasound (up to week 13 6/7) or that of the subsequent trimesters if the first trimester is not provided. If the date of the last menstruation agrees with the gestational age obtained through the ultrasound of the first trimester or of the subsequent trimesters, it can be used (39). Hospitalization During Pregnancy: Defined as admission to a hospital during pregnancy (40) Renal compromise: Defined as serum creatinine greater than or equal to 1.1 mg / dL (4). Placental abruption: Defined as a process consisting of premature detachment of the placenta characterized by vaginal bleeding, uterine hypertonicity or unsatisfactory fetal status associated with direct visualization of retroplacental hemorrhage or hematoma (41). Fetal: Small for gestational age fetus: defined as a newborn whose weight is less than the 10th percentile for gestational age (42). Preterm delivery: Defined as delivery before 37 weeks of gestation (43). Hypoxic / Ischemic Encephalopathy: defined as the presence of neurological dysfunction in the form of neonatal encephalopathy, associated with depression of the level of consciousness, respiratory depression, alteration of muscle tone and seizures, associated with suggestive findings on brain MRI (44). Search methods for identification of studies Electronic searches A comprehensive search was conducted to identify as many relevant studies as possible in the electronic databases. A combination of controlled vocabulary was used (MeSH, Emtree terms, Health Sciences, and descriptors (DeCS). The following electronic databases were searched: - Cochrane Central Register of Controlled Trials (CENTRAL). - MEDLINE, PubMed - EMBASE Ovid - LILACS (Health Sciences of Latin America and the Caribbean). Search for other resources The following resources were sought for additional studies: • International Clinical Trials Registry Platform (ICTRP) https://apps.who.int/trialsearch/AdvSearch.aspx • Gray literature: a search was carried out in the information system for gray literature in Europe “OpenGrey”. Manual search Abstracts of the following conferences were hand searched: - International Federation of Gynecology and Obstetrics (FIGO) (www.figo.org). - American College of Obstetricians and Gynecologists (ACOG) (www.acog.org). - Royal College of Obstetricians and Gynecologists (RCOG) (www.rcog.org.uk). - Colombian Federation of Obstetrics and Gynecology. (https://www.fecolsog.org/) Data extraction and analysis The following methods were used when the reports were identified: Study selection Two reviewers independently assessed the inclusion of all potential studies that were identified as a result of the search strategy. Relevance and adherence to the inclusion criteria were evaluated. If studies did not meet the inclusion criteria, they were not included and the reasons for exclusion were wrote. Any disagreement was resolved through discussion or, if necessary, a third reviewer was consulted. Data extraction and management A form for data extraction was designed. For chosen studies, two reviewers extracted data using the agreed form. Discrepancies were resolved through discussion or, if necessary, a third reviewer was consulted. The data was entered into the RevMan 2019 software and verified for accuracy. When the information on any of the previous points was not clear, an attempt was made to contact the authors and editors of the original studies and the journals where they were published to provide more details. Assessment of risk of bias in included studies The risk of bias from randomized clinical trials was assessed using the criteria described in RoB 2.0 bias assessment tool (45). Any disagreement was resolved by discussion or involving a third reviewer. RoB 2.0 risk assessment of biases Assessment of the quality of evidence using the GRADE system The quality of evidence was evaluated using the GRADE system as specified in the GRADE manual so as to assess the quality of evidence related to the outcomes of the main comparison. Antihypertensive withdrawal was defined as abrupt discontinuation of drug use, de-escalation of the drug until complete withdrawal or tapering of the drug dose compared to continuing established antihypertensive therapy, Placebo and Other interventions. A summary of the effect of the intervention and of the quality measurement for each of the next outcomes was developed using the GRADE system (Annexed tables 1 and 2). Measurement of treatment effect Dichotomous data The results were reported as a probability ratio (OR) with a 95% confidence interval (CI). Continuous data The mean difference (MD) was used if the results are measured in the same way within the included studies and the standardized mean difference (SMD) was used to combine trials measuring the same outcome, but with different methods. Assessment of missing data An intention-to-treat analysis was performed, that is, an attempt was made to include all participants assigned to each analysis group and all participants who were analyzed in the group to which they were assigned, regardless of whether or not they received the assigned intervention. The impact of including studies with high levels of missing data in the overall evaluation of treatment effects was explored using a sensitivity analysis. Assessment of heterogeneity Statistical heterogeneity was assessed using I2 values and Chi square test values. Heterogeneity was considered substantial if the I2 statistical value was greater than 40% or if there was a low p-value (less than 0.10) in the Chi-square test. Assessment of reporting bias Publication bias was assessed when ten or more studies were retrieved through the evaluation of the asymmetry of the funnel plot and the formal tests. For continuous variables, the test proposed by Egger was used (46), and for dichotomous results the test proposed by Harbord was used (47). Subgroup analysis and investigation of heterogeneity We explored the following potential sources of heterogeneity where it was considered that the effect size may have changed based on their results using subgroup analysis. 1. Definition of chronic arterial hypertension. Chronic arterial hypertension defined as SBP greater than or equal to 130 and DBP greater than or equal to 80 vs. defined as SBP greater than or equal to 140 and DBP greater than or equal to 90. 2. Subgroup of type of antihypertensive. alpha 2 agonists, calcium antagonists, alpha blockers, beta blockers, alpha adrenergic antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, vasodilators, and diuretics. 3. Etiology of hypertension. Primary hypertension vs. secondary hypertension. Data analysis Statistical analysis was performed using RevMan 2019, a fixed-effect meta-analysis was used to pool the data when it was reasonable to assume that the studies estimated the same underlying treatment effect, that is, when the studies examined the same intervention, and the populations and study methods were sufficiently similar. When there was sufficient clinical heterogeneity to have expected underlying treatment effects differed between studies or substantial statistical heterogeneity, a random effects meta-analysis was performed. The average effect of the random effects was assessed as the average range of possible treatment effects and the clinical implications of treatment effects that differed between trials was discussed. If the average effect was not clinically significant, the trials were not combined. If random effects analysis was used, the results were presented as the mean treatment effect and 95% confidence intervals and I2 estimates. Sensitivity analysis A sensitivity analysis was performed by type of studies and based on other aspects of the review that may had have an effect on the results, a sensitivity analysis was also performed to explore the inclusion of the effects of fixed or random effects analysis for the results with statistical heterogeneity