Aims: To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy. Methods: Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the Cochrane Library for randomized clinical trials from the establishment of the database to 15 July 2021 that were eligible for inclusion and analyzed the pharmaceuticals used for severe hypertension in pregnancy. Results: 29 relevant trials with 2,521 participants were involved. Compared with diazoxide in rate of achieving target blood pressure, other pharmaceuticals, including epoprostenol (RR:1.58, 95%CI:1.01-2.47), hydralazine\dihydralazine (RR:1.57, 95%CI:1.07-2.31), ketanserin (RR:1.67, 95%CI:1.09-2.55), labetalol (RR:1.54, 95%CI:1.04-2.28), nifedipine (RR:1.54, 95%CI:1.04-2.29), and urapidil (RR:1.57, 95%CI:1.00-2.47), were statistically significant in the rate of achieving target blood pressure. According to the SUCRA, diazoxide showed the best therapeutic effect, followed by nicardipine, nifedipine, labetalol, and nitroglycerine. The three pharmaceuticals with the worst therapeutic effect were ketanserin, hydralazine, and urapidil. It is worth noting that the high ranking of the top two pharmaceuticals, including diazoxide and nicardipine, comes from extremely low sample sizes. Other outcomes were reported in the main text. Conclusion: This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that the instability of hydralazine reducing blood pressure and the high benefit of labetalol with high dosages intakes should also be of concern to clinicians.

Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high burden of mortality and readmission rate making it one of the most significant public health challenges. Basic treatment strategies include diuretics for symptom relief and use of quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality. Despite compelling evidence of clinical benefit, guideline directed medical therapy is vastly underutilized in the real-world clinical practice. Other medications such as intravenous iron, ivabradine, hydralazine/nitrates and vericiguat may also have a role in certain subgroup of HFrEF patients. Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy and transcatheter mitral valve repair. This review provides a comprehensive overview of drug and device management approaches for patients with HFrEF, recommendations for initiation and titrations of therapies, and challenges associated with guideline directed medical therapy in the management of patients with HFrEF.

A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.

Hydralazine is a vasodilator used in the treatment of resistant hypertension. It is a safe and widely used antihypertensive medicine. Its common adverse effects include headache, rebound tachycardia, fluid retention, and angina. It is a rare cause of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with pulmonary and renal involvement. We report a case of a 74-year-old woman, with over eight years of use of hydralazine, who presented to the hospital with shortness of breath and cough. Blood work revealed deranged renal function with high creatinine levels. Serology workup was positive for anti-histone antibodies (AHA), anti-nuclear antibodies (ANA), myeloperoxidase (MPO) ANCA and proteinase-3 (PR-3) ANCA. Renal biopsy showed diffusely flattened tubular epithelium, focal micro vesicular degeneration, and focal loss of the brush border of the proximal tubular epithelium. Hydralazine was stopped and the patient was treated with corticosteroids, resulting in the resolution of her kidney injury.

Hydralazine is an antihypertensive medication that has been associated with drug-associated autoimmune syndromes like interstitial lung disease, pauci-immune glomerulonephritis, and hypocomplementemia. Hydralazine-induced ANCA-associated vasculitis and hydralazine induced positive antinuclear antibodies are rare. Clinical manifestations range from arthralgia, petechiae, or rash to multiorgan involvement. When presented as pulmonary-renal syndrome, it can be rapidly progressive and fatal. Here, we describe a case of hydralazine-associated vasculitis with rapidly progressive glomerulonephritis and highlight the importance of early diagnosis and prompt treatment.

Ageing is the process generated by senescent cells, free radicals, inflammation and other relevant factors. Ageing contributes to age-related diseases that affect the quality of life. People are interested in anti-ageing intervention and many scientists attempt to search for anti-ageing medicines. This review focused on describing in vivo anti-ageing activity of US-FDA-approved drugs and found that alogliptin, canagliflozin and metformin might produce anti-ageing activity via AMPK activation. Rapamycin and canagliflozin are capable to inhibit mTOR to promote lifespan. Atracurium, carnitine and statins act as DAF-16 activators, which potentially contribute to anti-ageing activity. Hydralazine, lisinopril, rosiglitazone and zidovudine may help stabilize genomic integrity to prolong life expectancy. Other indirect mechanisms, including insulin-lowering effect by acarbose and calcium channel blocking activity by verapamil may also promote longevity. Interestingly, some drugs (i.e., canagliflozin, metformin, rapamycin and acarbose) are likely to demonstrate a lifespan-promoting effect predominantly in male animals. These pre-clinical data might provide mechanistic and phenotypic perspectives to better understand the targets of anti-ageing interventions.

To evaluate the effect of continuous infusion of nicardipine on the management of uncontrolled blood pressure (BP) during postpartum period. This retrospective study included 209 women diagnosed in hospital with hypertensive disorders during pregnancy and had uncontrolled BP after delivery between January 2018 to December 2020 Uncontrolled BP was defined as persistent elevation of systolic BP ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg. Patients were divided into 2 groups: nicardipine (N = 53; continuous nicardipine infusion and additional bolus of labetalol or hydralazine) and control (N = 156; consecutive bolus of labetalol or hydralazine). BP data were analyzed using the Mann-Whitney U and χ2 tests by dividing the time interval of 4 hours by the delivery time. The highest BP trends showed that the mean values of both systolic and diastolic BP immediately before delivery were higher in the nicardipine group than in the control. After 8 to 12 hours following delivery, both systolic and diastolic BP were lower in the nicardipine group than in the control. Subsequently, 16 to 20 hours after delivery, both systolic and diastolic BP were significantly lower in the nicardipine group than in the control (137/80 vs 141/84 mm Hg). Initially, the proportions of uncontrolled BP in the nicardipine group were higher than those in the control; however, it then became lower at all time intervals 8 hours after delivery. The proportions of patients who received additional antihypertensive agents and the median cumulative dosages were lower in the nicardipine group than in the control. Continuous infusion of nicardipine can help manage uncontrolled BP during the postpartum period.

SARS-CoV-2 poses a great challenge toward mankind, majorly due to its evolution and frequently occurring variants. On the other hand, in human hosts, microRNA (miRNA) plays a vital role in replication and propagation during a viral infection and can control the biological processes. This may be essential for the progression of viral infection. Moreover, human miRNAs can play a therapeutic role in treatment of different viral diseases by binding to the target sites of the virus genome, thereby hindering the essential functioning of the virus. Motivated by this fact, we have hypothesized a new approach in order to identify human miRNAs that can target the mRNA (genome) of SARS-CoV-2 to degrade their protein synthesis. In this regard, the multiple sequence alignment technique Clustal Omega is used to align a complement of 2656 human miRNAs with the SARS-CoV-2 reference genome (mRNA). Thereafter, ranking of these aligned human miRNAs is performed with the help of a new scoring function that takes into account the (a) total number of nucleotide matches between the human miRNA and the SARS-CoV-2 genome, (b) number of consecutive nucleotide matches between the human miRNA and the SARS-CoV-2 genome, (c) number of nucleotide mismatches between the human miRNA and the SARS-CoV-2 genome, and (d) the difference in length before and after alignment of the human miRNA. As a result, from the 2656 ranked miRNAs, the top 20 human miRNAs are reported, which are targeting different coding and non-coding regions of the SARS-CoV-2 genome. Moreover, molecular docking of such human miRNAs with virus mRNA is performed to verify the efficacy of the interactions. Furthermore, 4 miRNAs out of the top 20 miRNAs are identified to have the seed region. In order to inhibit the virus, the key human targets of the seed regions may be targeted. Repurposable drugs like carfilzomib, bortezomib, hydralazine, and paclitaxel are identified for such purpose.

Large randomized controlled trials (RCTs) have led to major changes in the treatment of patients with heart failure and reduced left ventricular ejection fraction (HFrEF) and these advances are included in the recent European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) guidelines issued in 2021 and 2022, respectively. According to both guidelines, treatment of patients with HFrEF is based on the administration of four classes of drugs that reduce the primary endpoint of cardiovascular death and HF hospitalizations in RCTs: angiotensin-converting enzyme or angiotensin receptor neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors. Specific sequences of treatment are not recommended but emphasis is given to reaching treatment with all four drugs as early as possible. Further treatments are considered in selected patients including ivabradine, hydralazine nitrates, digoxin, and the new agent vericiguat. Specific treatments, mostly new, for cardiovascular and non-cardiovascular comorbidities are also given. The aim of this article is to compare the two recent guidelines issued by the ESC and ACC/AHA/HFSA and show the few differences and the many consistent recommendations, now more numerous given the evidence available for many new treatments.

Growing evidence indicates that skin injuries are a common complication of diabetes. However, the cellular and molecular mechanisms of high glucose (HG) environment trigger nitrosative stress-mediated inflammation and apoptosis in keratinocytes remains unknown. Here we investigated whether reactive nitrogen species (RNS) induced by HG environment restrain antioxidant activity, and mitochondrial dysfunction leading to inflammation, and apoptosis via stress signaling pathways in keratinocytes. Our results established that the HG environment enhanced the production of nitric oxide (NO) and peroxynitrite anion (ONOO-) by inducible NO synthase (iNOS) in keratinocytes. Overproduction of RNS in HG environment suppress the antioxidants activity leading to mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential (ΔΨm), increase in mitochondrial mass, decrease in mitochondrial transcription factor A(TFAM), increase in mitochondrial DNA (mtDNA) displacement loop (D-loop) and decrease in glycolytic flux concentration, which was attenuated by pharmacological inhibitors of NO/ONOO-, Nω-Nitro-l-argininemethyl ester hydrochloride (NAME)/hydralazine hydrochloride (Hyd.HCl). Excess production of RNS in HG environment restrained 8-oxoguanine DNA glycosylase-1 (OGG1) expression and increased 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA were regulated by NO or ONOO-. Further, HG-induced RNA production caused an increase in the production of inflammatory mediators accompanied by activation of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascade, lipid peroxidation (LPO), and protein carbonylation (PC) reactions followed by breakdown the cell-cell communication and apoptosis. Pre-treatment of cell with NAME/Hyd.HCl, diminished the expression of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3, inflammatory mediators, and attenuated apoptosis in keratinocytes. Together, our results indicated that excess production of RNS in HG environment triggered inflammation and apoptosis, mediated by activation of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascades in keratinocytes.

Hydralazine is a traditional antihypertensive drug that was developed several decades ago. Its most well-known effect is blood pressure lowering by arterial vasodilation. While mainly used an adjunct treatment for clinical hypertension or chronic heart failure, this old drug has also shown potential as a repurposing drug for the atherosclerosis vascular disease and various kidney diseases. Recent experimental studies suggest that hydralazine exerts antioxidative, anti-apoptotic, and HIF-1α stabilization effects for angiogenesis and vascular protection. Hydralazine also exerts reno-protective effects via its antioxidation, DNA demethylation, and anti-inflammation abilities. The above evidence provides advanced rationales for new applications of this drug beyond blood pressure lowering and arterial vasodilation. Here, we summarized the recent experimental advances in the use of hydralazine for either a vascular disease or kidney diseases, or both. Given the wide populations of people with cardiovascular and/or kidney diseases, future studies are worth validating the potential impacts of hydralazine on the clinical outcomes in selected patients.

Heart failure (HF) is associated with morbidity, rehospitalization and polypharmacy. The incidence rate of mortality in HF patients with polypharmacy is poorly studied. We examine the association of polypharmacy with mortality risk in incident hospitalized HF patients with a primary diagnosis after discharge from the hospital using Quebec administrative databases, Canada from 1999 to 2015. Polypharmacy, cardiovascular (CV) polypharmacy and non-CV polypharmacy were respectively defined as exposure to ≥ 10 drugs, ≥ 5 CV drugs and ≥ 5 non-CV drugs within three months prior to the case or the control selection date. We conducted a nested case-control study to estimate rate ratios (RR) of all-cause mortality using a multivariate conditional logistic regression during one-year of follow-up. We identified 12,242 HF patients with a mean age of 81.6 years. Neither CV polypharmacy (RR 0.97, 95%CI 0.82-1.15) nor non-CV polypharmacy (RR 0.93, 95%CI 0.77-1.12) were associated with lower mortality risk. However, all polypharmacy (RR 1.31, 95%CI 1.07-1.61) showed an association with mortality risk. Myocardial infarction, valvular disease, peripheral artery disease, diabetes, major bleeding, chronic kidney disease, high comorbidity score, high Frailty score, hydralazine and spironolactone users were associated with increasing mortality risk, ranging from 15 to 61%, while use of angiotensin II inhibitors, beta-blockers, statins, anticoagulant, and antiplatelets were associated with lower risk, ranging from 23 to 32%.

Hypertensive disorders in pregnancy (HDP) represent a spectrum of disease that affect women through pregnancy and the immediate postpartum period. These conditions are associated with significant morbidity and mortality during and after pregnancy and have been linked to cardiovascular disease later in life. The HDP spectrum includes gestational hypertension (HTN), preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, chronic HTN, and chronic HTN with superimposed preeclampsia. Low-dose aspirin is recommended as a preventive drug after 12 weeks' gestation in women who are at high risk of preeclampsia. In HDP, close blood pressure (BP) monitoring, laboratory evaluation, and fetal assessment are warranted. Labetalol and nifedipine extended release are first-line oral antihypertensives for outpatient BP management of chronic HTN; labetalol, hydralazine, and nifedipine immediate release are used for hospitalized patients. HDP may develop or progress in the postpartum period; continued vigilance is important in the puerperium.

Hydralazine-induced lupus leading to pancytopenia is an uncommon presentation and can have systemic effects on the body. We present the case of a 73-year-old male with complaints of fever, night sweats, and non-intentional weight loss. Complete blood count pathology review showed pancytopenia with no blasts. Detailed infectious disease workup, including Coccidioidomycosis and tuberculosis, was negative. Rheumatological workup including rheumatic factor, anti-smith, anti-double-stranded DNA antibodies, and anti-ribonuclear proteins, was negative. Anti-nuclear antibodies and anti-histone antibodies were found to be positive. This led to the diagnosis of hydralazine-induced lupus. Hence, hydralazine was immediately discontinued which led to rapid improvement.

Lymph capillary network can be expected to alter blood pressure via regulating interstitial electrolyte and volume balance. However, the pathophysiology of lymphatic vessel in hypertension is poorly understood. In this study, we examined lymph vessel function focusing on contractile response in hypertensive rats. It was found that thoracic ducts isolated from adult (10-14 wk old) spontaneously hypertensive rats (SHRs) exhibited increased agonist-mediated contraction compared with age-matched Wistar-Kyoto (WKY) rats, whereas lymphatic contractions in younger (4 wk old) SHRs, exhibiting normal blood pressure, were no different compared with age-matched control rats. Tight regulation of blood pressure with antihypertensive drugs (hydrochlorothiazide/hydralazine) did not prevent the augmented lymphatic contraction in adult SHRs; however, treatment of SHRs with angiotensin II (ANG II) type 1 receptor blocker (losartan) for 6 wk abolished the augmentation of lymphatic contractions. In addition, ANG II infusion in Wistar rat caused augmented lymphatic contractile responses in the thoracic duct. The augmented contractions in adult SHRs were diminished by a ROCK inhibitor (Y-27632). Consistently, the thoracic ducts in SHRs showed significantly higher phosphorylation of myosin phosphatase targeting protein-1 than WKY rats. Furthermore, gene expression profiling of adult SHR lymphatics showed marked loss of regulator of G-protein signaling 16 (RGS16) mRNA, which was confirmed by the real-time PCR. Treatment with the RGS inhibitor CCG-63808 enhanced contractions in thoracic ducts from Wistar rats, which were abolished by the ROCK inhibitor. It is concluded that lymphatic contractile function was enhanced in hypertensive model rats, which could be mediated by dysregulation of the ROCK pathway possibly through RGS16.NEW & NOTEWORTHY Lymph capillary controls interstitial electrolyte and volume balance, which may blunt increased blood pressure. However, the function of lymphatic vessel in hypertension is poorly understood. Our study showed that the lymphatic smooth muscle contractility is hyperreactive in two different hypertensive models. The lymphatic dysfunction could be mediated by dysregulation of ROCK pathway possibly through RGS16. The present finding supports a new concept showing the functional relationship between lymphatic contractile activity and hypertension.

The experiments described here examined the effects of reaction conditions, various additives, and local sequence on the formation and stability interstrand cross-links (ICLs) derived from the reaction of an apurinic/apyrimidinic (AP) site with the exocyclic amino group of an adenine residue on the opposing strand in duplex DNA. Cross-link formation was observed in a range of different buffers, with faster formation rates observed at pH 5. Inclusion of the base excision repair enzyme alkyladenine DNA glycosylase (hAAG) which binds tightly to AP-containing duplexes decreased, but did not completely prevent, formation of the dA-AP ICL. Formation of the dA-AP ICL was not altered by the presence of the biological metal ion Mg2+ or the biological thiol, glutathione. Several organocatalysts of imine formation did not enhance the rate of dA-AP ICL formation. Duplex length did not have a large effect on dA-AP yield, so long as the melting temperature of the duplex was not significantly below the reaction temperature (the duplex must remain hybridized for efficient ICL formation). Formation of the dA-AP ICL was examined in over 40 different sequences that varied the neighboring and opposing bases at the cross-linking site. The results indicate that ICL formation can occur in a wide variety of sequence contexts under physiological conditions. Formation of the dA-AP ICL was strongly inhibited by the aldehyde-trapping agents methoxyamine and hydralazine, by NaBH3CN, by the intercalator ethidium bromide, and by the minor groove-binding agent netropsin. ICL formation was inhibited to some extent in bicarbonate and Tris buffers. The dA-AP ICL showed substantial inherent stability under a variety of conditions and was not a substrate for AP-processing enzymes APE1 or Endo IV. Finally, we characterized cross-link formation in a small (11 bp) stem-loop (hairpin) structure and in DNA-RNA hybrid duplexes.

Hydralazine is a vasodilator used to treat hypertension, pre-eclampsia, and heart failure. The current article reviews the clinical pharmacokinetics (PK) of hydralazine, which can be useful for clinicians in optimizing its dose and dosing frequency to avoid adverse effects and unexpected interactions that could risk patients' lives.

To investigate the potential intraocular pressure (IOP)-lowering effects of nitric oxide (NO)-donating compounds in healthy canine eyes METHODS: A total of 79 dogs were divided into 3 groups in a masked, controlled and randomised study. Group N (n = 26) was administered 0.03% nitroglycerin in one eye and vehicle-control in the other, Group H (n = 26) was administered 0.1% hydralazine in one eye and vehicle-control in the other, while Group C (n = 27) received vehicle-control in both eyes (control group). Following eye drop administration, IOP was measured in both eyes at selected times (10-250 min), along with monitoring of heart rate and signs of ocular discomfort. Data was analysed with repeated measures mixed model and one-way ANOVA RESULTS: IOP was significantly reduced over the 4-h period with 0.03% nitroglycerin (p < 0.0001) but not 0.1% hydralazine (p = 0.520) when compared to contralateral vehicle-controlled eyes. IOP was reduced by up to 12% with 0.03% nitroglycerin from 10 to 70 min post-treatment; however, differences in IOP at individual time points were not statistically significant for either drug (p ≥ 0.133) as compared to contralateral vehicle-control eyes. No treatment group significantly affected heart rate (compared to Group C), and both treatment groups appeared well tolerated CONCLUSIONS: Both compounds were well-tolerated in healthy dogs. Nitroglycerin mildly reduced IOP in canine eyes, and further investigations are warranted in healthy and diseased states (e.g. glaucoma, ocular hypertension).

Drug-induced vasculitis (DIV) is a rare form of vasculitis related to the use of various drugs. DIV primarily affects small to medium size vessels, but it can potentially involve vessels of any size. Differentiating between primary systemic vasculitis and DIV can be challenging; however, it is crucial, so that the offending agent can be discontinued promptly.

Severe hypertension in pregnancy is a medical emergency, defined as systolic blood pressure (BP) ≥ 160 mm Hg and/or diastolic BP ≥ 110 mm Hg taken 15 minutes to 4 or more hours apart. Outside pregnancy, acute severe hypertension (HTN) is defined as a BP greater than 180/110 to 120 reproducible on 2 occasions. The lower threshold for severe HTN in pregnancy reflects the increased risk for adverse outcomes, particularly maternal stroke and death, and may be a source of under-recognition and treatment delay, particularly in nonobstetrical health care settings. Once a severe hypertension episode is recognized, antihypertensive therapy should be initiated as soon as feasibly possible, at least within 30 to 60 minutes. Intravenous (IV) labetalol, hydralazine, and oral immediate-release nifedipine are all recommended first-line agents and should be administered according to available institutional protocols and based on provider knowledge and familiarity.

We investigated the trends in the proportion of antihypertensive prescriptions listed in the guidelines for pregnant patients and their pregnancy outcomes before and after regulatory actions in Japan. This retrospective cohort study used the Japan Medical Data Center claims data from January 2005 to April 2020. We identified women who had delivered and had hypertensive disorders before childbirth. To evaluate the influence of regulatory actions (label revision in 2011 and guideline updates in 2014), we divided the study period into three terms based on the year of the last menstrual period. We assessed the time trend of the prescription proportion of antihypertensives and conducted multivariable logistic regression analyses to assess the impact of the investigation terms on pregnancy outcomes (preterm birth, cesarean section, emergency cesarean section, and Hemolysis, Elevated Liver enzymes, and Low Platelets syndrome). Among the 13,797 eligible patients, 1739 (12.6%) were treated with oral antihypertensives during pregnancy. Before the policy revisions, the most frequently prescribed antihypertensive medication was methyldopa, but after the label and guideline revisions, nifedipine was the most frequently prescribed. The trend in the prescription proportion of nifedipine increased (P < 0.001) and that of hydralazine decreased (P < 0.001), while those of methyldopa and labetalol showed no significant trend. The adjusted odds ratios for all four pregnancy outcomes showed no significant differences according to the investigation terms. By investigating the three terms before and after the label and guideline revisions, significant changes were identified in the trend of the prescription proportion for pregnant women-an increase in nifedipine and a decrease in hydralazine-but not in pregnancy outcomes.