Drug-Induced Liver Injury in Pregnancy: The U.S. Drug-Induced Liver Injury Network Experience.

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that ß-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.

The ability and safety of community-based health workers to safely initiate lifesaving therapies for pre-eclampsia in Ogun State, Nigeria: An analysis of 260 community treatments with MgSO4 and/or methyldopa.

OBJECTIVES: To evaluate community-based health workers' ability to identify cases of hypertension in pregnancy, safely deliver methyldopa and magnesium sulphate and make referrals when appropriate. STUDY DESIGN: This was part of Nigeria Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomized controlled trial (NCT01911494). Community-based Health Workers (CHW) recruited pregnant women from five Local Government Areas (clusters) and used mobile health aid for clinical assessment of pre-eclampsia. MAIN OUTCOME MEASURES: The primary outcome was the number of adverse events that occurred after the administration of magnesium sulphate and/or methyldopa to pregnant women by CHWs. FINDINGS: Of 8790 women receiving mobile health-guided care, community-based health workers in Nigeria provided 309 women with hypertension (4.2% of delivered women), and safely administered 142 doses of intramuscular magnesium sulphate. Community Heath Extension Workers (CHEWs) and nurses gave fifty-two and sixty-seven doses of intramuscular magnesium sulphate respectively, twenty-three doses were given by other health care workers (midwives, community health officers, health assistants). The high rate of administration by nurses can be explained by turf protection as well as their seniority within the health system. Also, CHEWs and nurses gave 124 doses of oral methyldopa and 126 urgent referrals were completed. There were no complications related to administration of treatment or referral. INTERPRETATION: These findings demonstrate the ability of community-based health workers to safely administer methyldopa and intramuscular magnesium sulphate. The use of task-sharing, therefore, could drastically reduce the three delays (triage, transport and treatment) associated with high maternal mortality and morbidity in rural communities in low- and middle-income countries.

The comparison of side effects of methyldopa, amlodipine, and metoprolol in pregnant women with chronic hypertension.

OBJECTIVE: The aim of the study was to compare the complication of Antihypertensive drug; in pregnant women with chronic hypertension. METHOD: This retrospective cohort study was performed on 300 pregnant women  with chronic hypertension. Results:  a relative risk of preeclampsia among methyldopa group was 3.45 times higher than the metoprolol, the relative risk of preterm labor was not significantly between methyldopa and metoprolol group, LBW, and IUGR in methyldopa and amlodipine groups . CONCLUSION: Methyldopa and amlodipine are associated with the least side effects in pregnant women treated for chronic hypertension.the incidence of preeclampsia was greater in methyldopa group.

Methyldopa as an inductor of postpartum depression and maternal blues: A review.

PURPOSE: Pregnancy and time period right after labour are connected with some dangerous states, such as: pregnancy-induced hypertension (PIH), which afflict 6-10 % of pregnant women and mood disorders where postpartum depression occurs among 10-15 % of women after labour and so-called baby blues afflicts around 43 % of them. Scientists tried to link those diseases which afflicts thousands of women per year, and the linking factor appears to be methyldopa which is the first choice treatment of PIH. Recent study showed that 778 % of pregnant women treated with methyldopa suffered to postpartum depression. Aim of this article is to delineate mechanisms through which methyldopa induce mood disorders. METHODS: Authors reviewed following databases for randomized controlled trials and review articles published up to February 2019: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. Keywords used to research were: postpartum depression, methyldopa, depression, baby blues, pregnancy-induced hypertension, gestational hypertension, VEGF, nitric oxide, prolactin, hyperprolactinaemia. Selection of studies was based on relevance, year of publication, and reliability of methodology. Authors included every study contributory to assessment of scale of the problem of postpartum depression and baby blues, along with connection of those diseases with usage of methyldopa. RESULTS: Methyldopa alterate neurotrophic factors levels, impairs cerebral blood flow, and through dopamine level reduction it impairs reward system and increase prolactin release. Moreover, methyldopa leads to catecholamines depletion which impairs neurons function and increase concentration of nitric oxide (NO) which have neurotoxic properties. CONCLUSIONS: Epidemiological, as well as pharmacological studies confirmed important role of methyldopa in induction of postpartum depression and baby blues through hormone alteration, reduced cerebral blood flow and neurons function impairment. This study proves how important for women's health is this problem and how complex is its mechanism.

Maternal and perinatal outcomes associated with the use of renin-angiotensin system (RAS) blockers for chronic hypertension in early pregnancy.

OBJECTIVE: Previous research reported greater risk of adverse perinatal outcomes associated with first trimester exposure to angiotensin converting enzyme inhibitors (ACEIs) in comparison to unexposed pregnancies among non-hypertensive women. We examined the relationship between first trimester exposure to ACEIs and angiotensin receptor blockers (ARBs), and maternal and perinatal outcomes, whilst controlling for the underlying hypertension. STUDY DESIGN: We performed a population-based cohort study among 130,061 pregnancies resulting in birth in NSW, Australia between 2005 and 2012. Birth data were linked to hospital discharge and pharmaceutical dispensing records. After restricting to women with chronic hypertension, 67 and 73 pregnancies exposed to ACEIs and ARBs respectively during the first trimester were compared with 316 pregnancies exposed to methyldopa. STUDY OUTCOMES: Preterm delivery, caesarean section, low birth weight, small for gestational age and Apgar score <7. RESULTS: Compared to pregnancies exposed to methyldopa, the adjusted odds ratio (aOR) for ACEI exposure was 0.5 (95% CI: 0.2-1.1) for preterm delivery, 1.6 (0.8-3.1) for caesarean section, 0.6 (0.2-1.3) for LBW and 0.8 (0.4-1.9) for SGA. The corresponding aORs and confidence intervals for ARB exposure were 0.7 (0.3-1.5), 1.2 (0.6-2.6), 1.3 (0.7-2.6), and 1.2 (0.6-2.4). CONCLUSION: No association between early pregnancy exposure to ACEIs and ARBs and perinatal outcomes was observed, however, the possibility of an association cannot be ruled out due to limited power. Nonetheless, this study suggests that the magnitude of risk is smaller than that reported previously.

Risk analysis of suicidal ideations and postpartum depression with antenatal alpha methyldopa use.

Out of the various risk factors for postpartum depression, use of pharmacotherapy during pregnancy is the most poorly understood. The present study aimed to establish risk of postpartum depression and suicidal ideations with antenatal use of alpha methyldopa. Out of the 100 postpartum women assessed, 77.78% of the women who were prescribed alpha methyldopa had significant postpartum depression. There was statistically significant risk of postpartum depression associated with alpha methyldopa (p = 0.026, OR = 6.45). There was no increased suicidal risk with use of alpha methyldopa in these women (p = 1.00).

Beyond anxiety and agitation: A clinical approach to akathisia.

BACKGROUND: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered. OBJECTIVE: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward. DISCUSSION: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.

Pregnancy Outcome After First Trimester Use of Methyldopa: A Prospective Cohort Study.

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4-4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth. CLINICAL TRIAL REGISTRATION: URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

Drug-induced liver injury with autoimmune features.

Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.

Tratamento farmacológico e intervencionista do sistema nervoso simpático / Pharmacological and interventional treatment of sympathetic system

o sistema nervoso autônomo contribui diretamente para uma série de atividades biológicas e está envolvido em inúmeras doenças. A hiperatividade simpática é um dos vários mecanismos envolvidos na patogênese da hipertensão arterial sistêmica (HAS) primária. A transmissão da informação nervosa através de sinapses é mediada por agentes químicos específicos conhecidos como neurotransmissores, representados pela acetilcolina e pelas catecolaminas. O bloqueio dos receptores pré e pós-sinapse permite que a ação de fárrnacos alcance sua plenitude no controle dos portadores de hiperati vidade simpática. Um percentual significativo de hipertensos são resistentes ao tratamento farrnacológico. A denervação simpática renal surgiu como estratégia terapêutica adjunta no controle de hipertensos resistentes ao tratamento clínico. Nos últimos cinco anos, diversos estudos demonstraram resultados consistentes na redução da pressão arterial. Diversas outras condições clínicas associam-se à hiperatividade do sistema adrenérgico, tais como a insuficiência cardíaca, o diabetes mellitus, a doença renal crônica, a síndrome da apneia e hipopneia obstrutiva do sono e as arritmias cardíacas. Nestes contextos, a redução da atividade simpática renal também mostrou-se ser benéfica em estudos clínicos iniciais. Uma variedade de dispositivos dedicados foram e estão sendo desenvolvidos com o objetivo de ampliar a segurança e a eficácia do método, além de facilitar o procedimento. Estudos multicêntricos, prospectivos, randomizados e controlados em andamento investigam desfechos como mortalidade cardiovascular, infarto agudo do miocárdio e acidente vascular cerebral em longo prazo.

The autonomic nervous system contributes directly to a number of biological activities and is involved in numerous diseases. Sympathetic hyperactivity is one of several mechanisms involved in the pathogenesis of primary hypertension. The transmission through the nerve synapses is mediated by specific chemical agents known as neurotransmitters represented by the acetylcholine and catecholarnine. Blockade of specific pre-and post-synapse receptors allows the treatment of patients with sympathetic hyperactivity. A large proportion of hypertensive patients are resistant to pharmacological treatment. Renal sympathetic denervation emerged as adjunctive therapeutic strategy in controlling hypertension resistant to medical treatrnent. ln the last five years, several studies have shown consistent results in lowering blood pressure. Several other clinica! conditions are associated with hyperactivity of the adrenergic system such as heart failure, diabetes mellitus, chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome and cardiac arrhythrnias. ln these contexts, the reduction in renal sympathetic activity also proved to be beneficial in initial clinical studies. A substantial variety of dedicated devices have been developed in order to reduce variability between operators, reduce renal artery manipulation, improve vessel contact, reduce radiation exposure and procedure time, and therefore improving safety and efficacy. Mu!ticenter, prospective, randomized, controlled trials are ongoing to investigate long term outcomes such as cardiovascular mortality, acute myocardial infarction and stroke.

Prenatal exposure to methyldopa leading to hypertensive crisis and cardiac failure in a neonate.

A 2-week-old infant with normal intracardiac anatomy presented to the emergency department in a hypertensive crisis with acute cardiac failure. Despite extensive evaluation, no underlying disease was found. The patient's hypertension and cardiac dysfunction resolved after 1 week of supportive care in the PICU, and she was discharged within 2 weeks of presentation. The patient's history revealed transplacental exposure to the α-adrenergic agonist methyldopa for 10 weeks before delivery. Her age at presentation and the self-limited nature of cardiac sequelae with complete resolution of cardiac dysfunction suggest withdrawal effects from this exposure. Whereas the rebound hypertensive effects of α-adrenergic agonists are well established in the adult population, this report shows an unusual adverse outcome of in utero exposure to methyldopa.

α-Methyldopa-induced hepatitis during the postpartum period.

A 34-year-old woman, with a history of pre-eclampsia, was diagnosed with α-methyldopa-induced hepatotoxicity, after she presented with severe jaundice and hepatitis 8 weeks following delivery. Laboratory investigations and liver biopsy ruled out other causes of hepatitis. She continued to improve clinically after cessation of α-methyldopa, and was discharged 10 days after admission. This case report emphasises that it may not be possible to predict which patients may develop α-methyldopa-induced hepatitis, hence regular monitoring of liver function tests during treatment should be implemented.

Beta-blockers increase the risk of being born small for gestational age or of being institutionalised during infancy.

OBJECTIVE: To compare infant outcomes between mothers with hypertension treated by beta-blockers alone and by methyldopa alone during pregnancy. DESIGN: Historical cohort study. SETTING: Saskatchewan, Canada. POPULATION: Women who delivered a singleton birth in Saskatchewan during the periods from 1 January 1980 to 30 June 1987 or from 1 January 1990 to 31 December 2005 (women who delivered between 1 July 1987 and 31 December 1989 were excluded because the information recorded on maternal drug use during pregnancy is incomplete) with a diagnosis of a hypertensive disorder during pregnancy, and who were dispensed only beta-blockers (n = 416) or only methyldopa (n = 1000). METHODS: Occurrences of adverse infant outcomes were compared between women who received beta-blockers only and women who received methyldopa only during pregnancy, first in all eligible women, and then in women with chronic hypertension and in women with gestational hypertension or pre-eclampsia/eclampsia, separately. Multiple logistic regression analyses were performed to adjust for potential confounding. MAIN OUTCOME MEASURES: Small for gestational age (SGA) < 10th percentile, SGA < 3rd percentile, preterm birth, stillbirth, institutionalisation for respiratory distress syndrome (RDS), sepsis, seizure during infancy, and infant death. RESULTS: Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for infants born to mothers with chronic hypertension who were dispensed beta-blockers only, as compared with infants born to mothers who were dispensed methyldopa only, during pregnancy were: 1.95 (1.21-3.15), 2.17 (1.06-4.44), and 2.17 (1.09-4.34), respectively, for SGA < 10th percentile, SGA < 3rd percentile, and being institutionalised during infancy. CONCLUSIONS: For infants born to mothers with chronic hypertension, compared with those treated by methyldopa alone, those treated by beta-blockers appear to be at increased rates of SGA and hospitalisation during infancy.

Association between labetalol use for hypertension in pregnancy and adverse infant outcomes.

OBJECTIVE: Labetalol and methyldopa are the two antihypertensive drugs most frequently used to control blood pressure for hypertensive disorders of pregnancy. The objective of this study was to assess if labetalol is associated with poor infant outcomes. STUDY DESIGN: Retrospective population-based cohort study using the linked maternal/infant databases in the Province of Saskatchewan. Women with a diagnosis of a hypertensive disorder of pregnancy who delivered a singleton in Saskatchewan from January 1, 1990 to December 31, 2005 and who were dispensed only labetalol or only methyldopa were included in the study. Occurrences of small for gestational age (SGA)<10th percentile, SGA<3rd percentile, preterm birth, stillbirth, hospitalization for respiratory distress syndrome (RDS), sepsis, and seizure during infancy, and infant death were compared. Multiple logistic regression analysis was performed to adjust for potential confounding. RESULTS: A total of 1223 eligible women were included in the final analysis. Among them, 300 received labetalol only and 923 received methyldopa only during pregnancy. For women with chronic hypertension, the rate of hospitalization for RDS, sepsis, and seizure during infancy was significantly higher for infants born to mothers who were dispensed labetalol only as compared with infants born to mothers who were dispensed methyldopa only (adjusted odds ratio (OR) 1.51, 95% confidence interval (CI) 1.02-2.22). CONCLUSION: Compared with methyldopa, the use of labetalol for chronic hypertension of pregnancy may be associated with increased rate of hospitalization during infancy.

Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa.

BACKGROUND: Pregnancy-induced hypertension (PIH) is associated with adverse fetal and maternal outcome. The role of medication to control blood pressure (BP) in mild to moderate PIH is controversial. AIMS: We conducted a prospective study to investigate whether pharmacological treatment of mild to moderate PIH is effective in improving maternal and fetal outcomes. METHODS: A total of 150 consecutive pregnant women without proteinuria and with physician-recorded systolic BP of 140-160 mmHg and/or diastolic BP of 90-105 mmHg on two occasions ≥6 h apart between 20 and 38 weeks of gestation were randomly allocated to receive either labetalol or methyldopa (50 patients each) plus standard care (treatment group) or only standard care (50 patients) (control group). RESULTS AND CONCLUSIONS: As compared to the control group, the treatment group had lower rates of severe PIH (28% vs. 10%, P = 0.005), proteinuria (28% vs. 12%, P = 0.016), hospitalization before term (28% vs. 14%, P = 0.041), and delivery by cesarean section (38% vs. 22%, P = 0.042). In a multivariable logistic regression model that adjusted for maternal age, weight, parity, previous PIH, and baseline hemoglobin, resting heart rate, and BP levels, antihypertensive therapy was associated with a lower incidence of adverse maternal events (P = 0.011). Compared to the control group, the treatment group had lower incidence of SGA babies (40% vs. 23%, P = 0.033), preterm birth (36% vs. 14%, P = 0.002), and admission to neonatal unit (30% vs. 15%, P = 0.036). After adjustment for maternal age, weight, baseline hemoglobin, resting heart rate, BP level, parity and previous history of PIH, fetal death, preterm delivery or SGA baby, antihypertensive therapy was associated with a lower incidence of adverse perinatal events (P = 0.016). Maternal and perinatal mortality rates were not significantly different between treatment and control groups. In conclusion, pharmacological treatment of mild to moderate PIH is associated with lower rate of some maternal and fetal-neonatal non-fatal adverse events compared to no routine use of antihypertensive therapy.

Hepatotoxicity of alpha-methyldopa in pregnancy.

Alpha-methyldopa is one of the most widely prescribed antihypertensive agents used during pregnancy. Despite its known potential hepatotoxicity, there have been only a few reports describing hepatotoxicity with the use of this drug during pregnancy. We report here a new case of acute hepatitis in a pregnant woman related to the use of alpha-methyldopa, and briefly review the literature on alpha-methyldopa-induced hepatotoxicity in pregnancy.

Hipertensión pulmonar poscapilar tras administración de antiinflamatorios no esteroideos y antihipertensivos / Congestive pulmonary hypertension following the admi- nistration of NSAIDs and anti-Hypertension drugs

La hipertensión arterial sistémica produce un aumento de la presión en las cavidades izquierdas cardiacas que, de forma retrógrada, puede conducir a una hipertensión pulmonar. Entre las causas reconocidas de hipertensión arterial sistémica se encuentran un número importante de fármacos de uso habitual. Presentamos el caso de una mujer puérpera que desarrolló HTA yHTP y proponemos como causa de las mismas, la administración demetilergometrina e ibuprofeno, que después se perpetuó por la asociación de metildopa y labetalol (AU)

The systemic hypertension produces an increase in pressure of left cardiac cavities that can lead to pulmonary hypertension. Many drugs are recognized cause of systemic hypertension. We report the case of a puerperae woman who developed pulmonary and systemic hypertension and we propose the administration of methylergometrine and ibuprofen and then methyldopa and labetalol as the cause of hypertension (AU)

Antihypertensive treatment during pregnancy and functional development at primary school age in a historical cohort study.

OBJECTIVE: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment. DESIGN: Historical cohort study. SETTING: Twelve Dutch hospital departments of obstetrics. POPULATION: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension. METHODS: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures. MAIN OUTCOME MEASURES: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age. RESULTS: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups. CONCLUSIONS: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.