Background: Perioral muscle function, which influences maxillofacial growth and tooth position, can be affected in patients with oral clefts due to their inherent anatomical characteristics and the multiple surgical corrections performed. This research aims to (1) compare the maximum oral muscle pressure of subjects with and without isolated cleft palate (CP) or unilateral cleft lip and palate (UCLP), (2) investigate its influence on their dentoalveolar characteristics, and (3) investigate the influence of functional habits on the maximum oral muscle pressure in patients with and without cleft. Material and methods: Subjects with and without CP and UCLP seeking treatment at the Department of Orthodontics of University Hospitals Leuven between January 2021 and August 2022 were invited to participate. The Iowa Oral Performance Instrument (IOPI) was used to measure their maximum tongue, lip, and cheek pressure. An imbalance score was calculated to express the relationship between tongue and lip pressure. Upper and lower intercanine (ICD) and intermolar distance (IMD) were measured on 3D digital dental casts, and the presence of functional habits was reported by the patients. The data were analyzed with multivariable linear models, correcting for age and gender. Results: 44 subjects with CP or UCLP (mean age: 12.00 years) and 104 non-affected patients (mean age: 11.13 years) were included. No significant differences in maximum oral muscle pressure or imbalance score were detected between controls and clefts or between cleft types. Significantly smaller upper ICDs and larger upper and lower IMDs were found in patients with clefts. A significant difference between controls and clefts was found in the relationship between oral muscle pressure and transversal jaw width. In cleft patients, the higher the maximum tongue pressure, the wider the upper and lower IMD, the higher the lip pressure, the smaller the upper and lower ICD and IMD, and the higher the imbalance score, the larger the upper and lower IMD and lower ICD. An imbalance favoring the tongue was found in cleft patients. The influence of functional habits on the maximum oral muscle pressure was not statistically different between clefts and controls. Conclusion: Patients with CP or UCLP did not present reduced maximum oral muscle pressure compared with patients without a cleft. In cleft patients, tongue pressure was consistently greater than lip pressure, and those who presented a larger maxillary width presented systematically higher imbalance scores (favoring the tongue) than those with narrow maxillae. Therefore, the influence of slow maxillary expansion on maximum oral muscle pressure in cleft patients should not be underestimated. An appropriate lip and tongue function is indispensable for speech and non-verbal oral functions such as swallowing. Large discrepancies in the activity of perioral muscles such as the orbicularis oris, buccinator, or tongue can affect oral aesthetics and ultimately contribute to a deterioration of the patient’s oral health-related quality of life  compare the maximum tongue, lip, and cheek muscle pressure and the imbalance of intra and extraoral muscles of subjects with and without CP or UCLP; (2) investigate the influence of the maximum oral muscle pressure and muscle imbalance on the dentoalveolar characteristics; and (3) examine the influence of functional habits on the maximum oral muscle pressure of both groups.The protocol of this prospective comparative study was defined prior to the start and approved by the Ethics Committee of University Hospitals Leuven and KU Leuven University, Belgium, with registration number s64829. Informed consent was obtained from all the participating subjects and their parents/guardians before enrollment in the study.In the cleft group, subjects with CP and UCLP, under the age of 18 and of self-reported European descent, seeking treatment at the Department of Oral Health Sciences—Orthodontics of University Hospitals Leuven between January 2021 and August 2022 were invited to participate. Subjects presenting only submucosal clefts, only clefts of the lip or the alveolar bone, bilateral cleft lip and palate, the Robin sequence, and have a confirmed diagnosis of a syndromic disorder or pathogenic mutations were excluded.All the included cleft patients were operated on by the same two surgeons at the same hospital with the following surgical protocol: In patients with UCLP, lip closure was performed at the age of 3 months using a modified Millard’s technique. In patients with CP and UCLP, soft palate closure took place at 12 months-old by using a modified Veau–Wardill–Kilner push-back technique with supraperiosteal dissection and hard palate closure between the ages of 5 and 7 years in order to minimize maxillary growth restriction due to scar tissue by using the modified von Langenbeck procedure. It is important to remark that cleft patients undergo orthodontic maxillary expansion on two occasions: before the hard palate closure and before the secondary alveolar bone graft, normally planned around the age of 9 to facilitate the eruption of the maxillary canines.In the control group, subjects without oral clefts, muscular diseases, or syndromes, aged under 18 years and of self-reported European descent, seeking treatment at the same department between October 2021 and November 2021, were invited to participate. This control group, composed at random over two months, represents the ‘average’ orthodontic patient.® . The following parameters were measured on the casts: intercanine and intermolar distance , overjeThe following functional habits were clinically evaluated: the patient’s swallowing pattern (mature or infantile), the position of the tongue at rest , and the competence of the lips (competent or not). Additionally, the following parafunctions were verbally asked about and, if possible, clinically checked: nail biting, pen chewing, thumb sucking, and bruxism.Perioral muscle pressure was measured with the Iowa oral performance instrument (IOPI) ,17, whicAn imbalance score, previously described in the literature , was useThe first aim of this research was to compare the maximum tongue, lip, and cheek pressure of subjects with and without cleft lip and/or palate. For this, multivariable linear models were used, modeling the muscle pressure as the response variable and the type of patient (cleft or non-cleft) as the explanatory variable of interest. Age and gender were included as covariates to account for possible confounding.t-tests were used for pairwise comparison.For the comparison of the transversal width (ICD and IMD) in the upper and lower jaws of subjects with and without clefts, a series of To investigate the influence of oral muscle pressure on dentoalveolar characteristics in patients with and without cleft (second aim), multivariable linear models were also used, and again, age and gender were included as covariates to account for possible confounding. The dentoalveolar characteristics were divided into two big groups: transversal width (ICM and IMD) and occlusal parameters , with these dentoalveolar characteristics as the response variable. The type of patient (cleft or non-cleft), muscle pressure, and the interaction between both terms were included in the explanatory model. A similar analysis was performed, defining the three patient groups as control, CP, or UCLP.The third aim was to investigate the influence of functional habits on oral muscle pressure in patients with and without cleft palates. Multivariable linear models were also used, and age and gender were included as covariates to account for possible confounding. The regression analyses modeled muscle pressure as the response variable, type of patient (cleft or non-cleft), functional habits (dichotomous variable), and the interaction between both terms in the explanatory model.Analyses were performed with SAS software (version 9.4 of the SAS System for Windows). A probability level of <0.05 was considered significant.Forty-four cleft patients were included . 16 and 28 subjects presented CP and UCLP, respectively. Of the CP patients, 7 presented a cleft of the soft palate only. From the UCLP subjects, 17 presented the cleft on the right side, and 11 presented Simonart’s band. Three of the UCLP patients had undergone presurgical nasoalveolar molding (PNAM), and one UCLP patient had used lip straps before the surgical lip closure.The control group consisted of 104 patients . p = 0.019, Fisher’s Exact test), which was expected since isolated CP is more common in women while UCLP occurs more frequently in men [p = 0.026, Mann–Whitney U test). Since literature shows that oral strength differs between males and females and that it increases with age in healthy subjects [Gender distribution was significantly different between the cleft and non-cleft groups  of the myofunctional outcome parameters  of the 5 observers was 0.803.Statistically significant differences were found between the control and cleft groups regarding maximum tongue pressure on the sagittal (right and left) occlusion, whereby a larger tongue pressure led to a tendency towards mesio-occlusion in patients with cleft compared to controls. The effect of maximum lip pressure was significantly different between controls versus cleft, controls versus CP, and controls versus UCLP for the right sagittal occlusion, whereby a larger lip pressure led to a tendency towards disto-occlusion in the cleft group. On the left side, the same effect was seen in patients with UCLP compared to controls. This can be explained by the increased occurrence of the unilateral variant on the right side. Significant differences were also observed between clefts and controls regarding the effect of the imbalance score on right occlusion: the higher the imbalance score in cleft patients (more tongue than lip pressure), the greater the tendency to mesio-occlusion. Additionally, the higher the imbalance score, the greater the tendency towards mesio-occlusion on the right and left sides in patients with UCLP compared to controls. A significant difference was seen between controls and CP and between CP and UCLP regarding overbite: the higher the imbalance score, the more tendency there is towards an open bite in CP. Significant differences were found between controls and UCLP regarding the effect of maximum right and left cheek pressure on overjet: the higher the cheek pressure, the more negative the overjet . A significant difference was seen between controls and cleft patients regarding right cheek pressure: the higher the right cheek pressure in cleft patients, the higher the chance of a cross bite.Finally, the influence of the observed functional habits on the maximum oral muscle pressure was statistically different between cleft and controls , but thiThis prospective study measures the maximum pressure of the lips, tongue, and cheeks in 44 subjects with CP and UCLP, comparing it with that of a non-affected control group consisting of 104 subjects, which is a very large control group in comparison to similar studies ,12,13,14Important to note is that 11 of the 28 included UCLP patients (39%) had a Simonart’s band on the cleft side, which according to the literature has a minor positive effect on the facial pattern, reduces the need for the secondary nose and lip repair , and reqIt is relevant to take into consideration that all cleft patients included in this study were operated on by the same two surgeons at the same hospital, following the same surgical protocol. However, between 2012 and 2013, a new surgical protocol for lip and palate repair was gradually implemented by the Cleft Team of University Hospitals Leuven. In the new surgical protocol, the hard palate is closed using a vomer flap at the time of lip repair. The repair of the soft palate still takes place at 10–12 months old, but no longer by supra-periosteal push-back; radical intravelar veloplasty as described by Sommerlad  is used The present study also explores the influence of the maximum oral muscle pressure on jaw width, measured by ICD and IMD. Significantly smaller upper ICDs and larger upper and lower IMDs were found in cleft patients compared with controls. It is important to remark that 19 of the 44 included cleft patients  (5 with CP and 14 with UCLP) had previously undergone interceptive orthodontic treatment with removable expansion plates, while only 8 of the 104 control patients (7.69%) had undergone interceptive expansion of the maxilla, which can influence the outcome. Early orthodontic treatment in cleft patients often overexpands the upper jaw, having more effect at the height of the molars than the canines , since tFurthermore, since we measured jaw width with 32 dental landmarks depending on the dentition stage, we can also make statements regarding tooth position. For example, it can be concluded that the higher the tongue pressure, the more the permanent molars are inclined buccally in patients with CP. This is also true for the canines and molars in the upper jaw in UCLP patients.The functional harmony and balance of the perioral muscles are critical not only in craniofacial growth and development but also in the position and inclination of the teeth. According to the equilibrium theory, teeth receive intraoral and extraoral muscle forces . A lack However, perioral muscle pressure at rest is considered to be more crucial than that exerted during function ,32, sincThis study also investigates the potential relationship between oral muscle pressure and sagittal occlusion, overjet, overbite, and cross bite in patients with and without clefts. The effect of the tongue on sagittal occlusion was significantly different between patients with and without cleft: in cleft patients, a greater tongue pressure led to more mesio-occlusion. Patients with cleft palate often present a skeletal and dental class III relationship due to the underdevelopment of the maxilla , caused The effect of the maximum lip pressure on the occlusion was significantly different between the controls and clefts: a greater lip pressure led to more disto-occlusion on the right side in the total cleft group, the CP group, and the UCLP group compared to the control group. The same effect was seen on the left side in the UCLP group compared to the controls. This can be explained by the increased occurrence of the unilateral variant on the right side. The findings of the cleft group could be due to compensatory movements of the lower lip, a more prominent lower lip, or a higher stomion position. The literature reports both a reduced range of upper lip movement  and compThe present research found a significant difference between the cleft and control groups regarding the right cheek pressure: the higher the right cheek pressure, the greater the chance of a cross bite being present. This could be explained by the presence of a cleft on the right side in 17 of the 28 UCLP patients. Literature is controversial on this topic. While Kecik et al.  also fouThe present study also looked into the relationship between maximum oral muscle pressure and functional habits in control and cleft patients. The influence of the swallowing pattern, resting position of lips and tongue, and several parafunctions on the maximum oral muscle pressure was not statistically different between the groups.In addition, it would also have been useful to know whether the patients had undergone speech therapy since this could influence the myofunctional results and can be seen as a limitation. Furthermore, the presence of scar tissue at the level of the lips and the palate, as well as the shape of the palate, could also play a role in the measurement of tral muscle pressure. These aspects were also not investigated in this study.Finally, the results of this study may have some clinical implications regarding early orthodontic expansion in patients with CP and UCLP. Maxillary expansion in patients with clefts is essential as it contributes to speech development, masticatory function, tooth eruption, and stabilization of the dental arches. However, maxillary expansion has been reported to relapse in 80% of patients with cleft ,45, sincPatients with cleft lip and/or palate did not present reduced maximum oral muscle pressure compared with patients without this condition. An imbalance favoring the tongue (the tongue pressure is greater than the lip pressure) was found in both patients with and without clefts. Patients with CP and UCLP with a larger transversal maxillary width presented systematically higher imbalance scores (favoring the tongue) than those with narrow maxillae. Therefore, the influence of slow maxillary expansion on maximum oral muscle pressure in cleft patients should not be underestimated. It is important for cleft teams to take these myofunctional aspects into consideration in the treatment of patients with cleft lip and/or palate, especially regarding orthodontic treatment planning.


Background: Preeclampsia is a highly prevalent disease among pregnant women. In the event of hypertensive emergency, nifedipine, labetalol, and hydralazine are assigned as first-line therapies in preeclampsia. Further studies are needed to compare the effectiveness of these drugs to find the most cost-effective drug with minimal side effects. This study aimed to compare the effectiveness of these drugs in lowering blood pressure during hypertensive emergencies in severe preeclampsia.Methods: 60 pregnant women with severe preeclampsia were recruited in this multiple centre double-blind randomized clinical trial from May 2021 to April 2022 in Indonesia. The patients were divided equally into three groups and treated with three doses of nifedipine, labetalol, and hydralazine, respectively within one hour with 20 minutes interval. The effectiveness was measured based on systolic and diastolic blood pressures, and mean arterial pressure (MAP). The observation was carried out until five hours post-third dose administration.  Results: The blood pressure was reduced significantly after the administration of the first to the third dose of each antihypertensive (p<0.05). A single dose administration, four, one, and three patients had 20% MAP reduction in nifedipine, labetalol, and hydralazine group. Three, seven, and one patient had a failure of reaching 20% MAP reduction even after receiving the third dose. The effectiveness of the drugs to achieve 20% reduction of MAP could be ranked as follows: nifedipine>labetalol>hydralazine  for single dose and hydralazine>nifedipine>labetalol  for triple dose.Conclusions: Nifedipine is the most effective drug to reduce the blood pressure when single dose administration is used, but requires more doses to further reduce the blood pressure. Hydralazine is the most effective when the drug administration is maxed up to three doses within 60 minutes with 20 minutes interval.Thai Clinical Trials Registry (TCTR): TCTR20221014007 (14/10/2022) The main cause of preeclampsia is unknown and the disease is therefore also called the disease of theory. As a result, the guidelines of preeclampsia management are updated and changed from time to time. Research continues to be updated to find the best formulation for diagnosis and management with the main aim to provide the management with the most optimal outcome for the mother and foetus. Termination of pregnancy is still considered the gold standard in severe preeclampsia, but this becomes a problem when the pregnancy is still premature as it can increase the infant mortality rate.Preeclampsia and eclampsia are major problems in obstetric cares. Preeclampsia is one of the main causes of maternal morbidity and mortality in addition to infection and bleeding with the prevalence rate between 5–8% among pregnant women. To date, ACOG has offered nifedipine, labetalol, or hydralazine as the antihypertensive emergency in preeclampsia. In June 2020, ACOG issued a statement that women with gestational hypertension presenting with high blood pressure (severe range) should be treated as same as severe preeclampsia.High blood pressure is the main indicator in the diagnosis of preeclampsia. Treatment of severe preeclampsia requires anticonvulsant and antihypertensive drugs. The purpose of administering antihypertensive drugs is to prevent cerebral bleeding. The American Congress of Obstetricians and Gynaecologists (ACOG) states that pregnant women with systolic blood pressure 160 mmHg and/or diastolic 110 mmHg that persist for 15 minutes should be considered an emergency condition and receive antihypertensives immediately, no later than 30 minutes. The target for MAP reduction in patients with severe preeclampsia is around 20–25%. This aims to maintain adequate uteroplacental circulation for the foetus. If blood pressure is reduced too low, there will be a sharp decrease in placental perfusion resulting in foetal distress, while the main goal of the management of preeclampsia is not only centred on the mother, but also on the outcome of the baby.An indicator of a decrease in blood pressure in patients with severe preeclampsia is the mean arterial pressure (MAP). MAP is obtained by the formula of twice the diastolic pressure plus one systolic pressure, then divided by three. Although there is little information regarding the use of calcium channel blockers, several studies have shown that oral nifedipine can also be considered as first-line therapy, especially when intravenous access is difficult. However, further studies are needed to compare the effectiveness of these three drugs with the aim of finding cost-effective drugs with minimal side effects, and right on target.Recommendations for antihypertensive drugs in preeclampsia are changing rapidly. Multiple antihypertensive drugs have been listed as drugs of choice for the treatment of severe preeclampsia but then excluded due to inconsistent treatment outcomes. Intravenous labetalol and intravenous hydralazine have long been considered as first-line therapy in hypertensive emergencies, severe hypertension in pregnant women, and in the postpartum period., Hydralazine and labetalol are considered to have a balanced effectiveness and side effect to achieve target blood pressure (systolic blood pressure 140–150 mmHg and diastolic blood pressure 90–100 mmHg) in preeclampsia., However, labetalol lowered blood pressure more rapidly than hydralazine. Another study comparing nifedipine and labetalol showed that these two drugs had the same effectiveness in achieving target blood pressures (systolic blood pressure 120–150 mmHg and diastolic blood pressure 70−100 mmHg) within 6 h with no adverse outcomes; 84% women vs 77% women with p=0.05. However, single-use nifedipine was more effective than labetalol.Previous studies on the effectiveness of these three drugs showed mixed results.In our preliminary study, the emergency antihypertensive drugs in severe preeclampsia that are often used in the Arifin Achmad Hospital, Riau Province of Indonesia and the affiliated hospitals of Faculty of Medicine, Universitas Riau, are nifedipine and methyldopa. There has never been a standardized study or observation on the safety and effectiveness of antihypertensive drugs in Indonesian population. Therefore, this study was conducted to compare the effectiveness of oral nifedipine, and intravenous labetalol and intravenous hydralazine as antihypertensives in severe preeclampsia.This study was a double-blind, randomized clinical trial to compare the effectiveness of oral nifedipine, intravenous labetalol, and intravenous hydralazine as antihypertensive emergency in severe preeclampsia. The multicentre study was conducted at four hospitals at Riau Province of Indonesia, Arifin Achmad Hospital, Tengku Rafian Siak Sri Indrapura Hospital, Dumai Hospital, and Bengkalis Hospital, from May 2021 to April 2022. These hospitals were chosen because they are affiliated with Faculty of Medicine, Universitas Riau.TCTR20221014007 (approved on 14 October 2022). This clinical trial was registered retrospectively in TCTR since the protocol of the study has been registered locally and this following the Indonesia law. All patients gave written informed consent before the enrolment. This study is reported in line with the CONSORT guidelines.The protocol of the study was approved on 28 May 2021 by the Medical and Health Research Ethics Unit, Faculty of Medicine, Universitas Riau with the number B/045/UN19.5.1.1.8/UEPKK/2021. This clinical trial has been registered at Thai Clinical Trials Registry (TCTR) with identification number isx1-x2 is the difference of the score between groups that considered significant (10) and S is standard deviation e between groups.The severe preeclampsia patients were recruited consecutively from populations that met the inclusion criteria. The minimal sample size of the study was 13 patients for each arm. This number based on calculation based on formula:However, a total of 20 severe preeclampsia patients were recruited for each group to prevent underpower due to drop-out and therefore there were 60 patients included in this study. The severe preeclampsia was defined as pregnant women with systolic blood pressure ≥160 mmHg or diastolic ≥110 mmHg that persisted for 15 minutes. Inclusion criteria were: (a) severe preeclampsia patient with 28–34-week gestation; (b) had live foetus; (c) upper arm circumference 23.5–33 cm; and (d) haemoglobin level at least 10.5 g/dL. All severe preeclampsia patients with decreased consciousness; had complications such as eclampsia, HELLP syndrome, kidney failure, or acute pulmonary oedema; in labour; received antihypertensive therapy in the last 12 hours; had an allergy to the trial drugs; and had asthma and heart disease were excluded. In this study the drop-out criteria were: the mother experienced allergy symptoms, had labour, or emergency symptoms such as placental abruption and foetal distress during the study.Randomizer software. Simple randomization was employed. In brief, 60 kits were prepared by the authors and were labelled 1 to 60 and each of kit containing three tables and three ampoules with the same sizes and colours. Kits no 1–20, 21–40 and 41–60 contained nifedipine, labetalol and hydralazine, respectively. For example, for one nifedipine kit, it contained 3 nifedipine tablets and 3 ampoules of placebo liquid. An author created the random sequence list consisting who will receive the kit no 1 until 60 based on random sequences provided byRandomizer software. For example, if the list from the software run was 41, 23, 4 and soon, the patient who arrived first, second and third to the hospital would be given kit no 41, 23 and 4, respectively. Each drug was administered 3 doses within 60 minutes . Each dose of the drug contained: oral nifedipine (20 mg), intravenous labetalol (20 mg in 10 ml of sodium chloride 0.9%) and intravenous hydralazine (10 mg in 10 ml of sodium chloride 0.9%). Since the study consisted multiple healthcare centers, patient enrolment was conducted in one hospital at one time based on allocated time. Therefore, there were no separation of the sequence list between centres.All severe preeclampsia patients who came to the hospitals were subjected to anamnesis, physical and laboratories examination and then selected based on predetermined inclusion criteria. Blood pressure measurements were carried out using a digital sphygmomanometer with the Omron 7600T brand. The patient was asked to sit and rest for 10 minutes, the measurement was conducted twice on the arm with a distance period of 15 minutes, and the data taken was the second measurement. If the patients met the requirements, they were asked to participate in the study and all patients have to sign the written informed consent before the enrolment. The assigned group was computerized randomized usingThe enrolment of the patient was conducted by the doctors in each centre. The doctors have been informed about the study and have been trained. The doctors and patients did not know the drugs contained in the kit. The doctors were instructed to administrate one pair of drugs  for each time. The blood pressure was assessed 20 minutes after each administration. If the blood pressure did not meet the MAP target, the second pair of drugs (one tablet and one ampoule injection) was given and the blood pressure was reassessed in 20 minutes until the third pair of the drugs. The blood pressure was re-assessed 60 min post-first dose, 2, 4 and 6 h post-first dose. Therefore, the blood pressure was measured seven times as follows: (1) minute 0 (pre-treatment); (2) 20 min post-first dose; (3) 20 min post-second dose ; (4) 20 min post-third dose ; (5) 2 h post-first dose; (6) 4 h post-first dose; and (7) 6 h post-first dose.The technique of administering magnesium sulphate and dexamethasone was uniform in all patients. If the MAP was nor reached after the third dose, the patient was treated with other drugs and excluded from the final analysis.The end points of this study were: (a) systolic blood pressure; (b) diastolic blood pressure; (c) MAP; and (d) side effects.SPSS software version 22 .Characteristics of patients from each group were tested for normality. The normality of data was measured using the Kolmogorov-Smirnov test. The data that had normal distribution were analysed using one-way ANOVA and followed by post hoc analyses. The data that did not distribute normally were analysed using Kruskal-Wallis and Friedmann followed by post hoc analyses. Comparison of the effectiveness of the three drugs was tested using N-Gain analysis. To determine how far the differences exist, Cohen's d effect size analysis was used. Further analysis with Kaplan-Meier survival was conducted. Statistical analysis was performed using Patients were recruited from the population that met the inclusion criteria and were willing to participate in the study by signing an informed consent. Patients were then monitored closely and periodically according to the study protocol. The number of patients for each step of enrolment, allocation, follow-up and analysis are presented inThe study was conducted on 60 patients with severe preeclampsia and they were divided into 3 groups: 20 patients in the nifedipine group, 20 patients in the labetalol group, and 20 patients in the hydralazine group.We recruited 60 severe preeclampsia patients and were divided randomly to receive nifedipine, labetalol and hydralazine. The characteristics of the patients including age, gravida, gestational age (gestation), upper arm circumference (UAC), systolic, diastolic, MAP, pulse, and foetal heart rate of each group are presented inData regarding the dose required for nifedipine, labetalol, and hydralazine to reach the target MAP (20% reduction) are presented inWe assessed the effectiveness of nifedipine, labetalol, and hydralazine to reduce the systolic and diastolic blood pressure where the data were treated as numerically to provided more detailed blood pressure reduction.NifedipineThe effectivity of nifedipine to reduce the systolic, diastolic and MAP is presented inThe changes of the mean systolic, diastolic and MAP are presented inLabetalolLabetalol decreased systolic blood pressure the most and significantly at 20 min post the first and the third dose (13.38 and 12.00 mmHg) . The sysHydralazineEffectivity of hydralazine in lowering the blood pressure has been presented in these three drugs had medium effectiveness in lowering blood pressure to achieve the target MAP (20%). Meanwhile, if referred to Hake criteria, nifedipine is highly effective, while labetalol and hydralazine are less effective in achieving a 20% MAP reduction. We also found significant difference of the MAP among the three drugs when administered in a single dose with p=0.037 based on Kruskal-Wallis test   . Based o=0.009) . Signifi=0.009) .The presence of ten side effects  was assessed following the administration of all three drugs. No patients treated with labetalol and hydralazine complained the side effect. Among patients treated with nifedipine, no side effects were reported by the patient except tachycardia. The latest ACOG bulletin guidelines did not mention the target blood pressure and only mentioned the blood pressure threshold that clinicians should to achieve. This present study was the first to report the direct comparison of the effectiveness of nifedipine, labetalol, and hydralazine together. In our study, a 20-25% decrease in MAP from baseline was considered the target blood pressure to be achieved. We also processed the data numerically so that a decrease of 1 mmHg was calculated and analysed to produce a detailed outcome. The blood pressure and pulse rate of the patients at the baseline are similar to previous studies studying the severe preeclampsia.– No characteristic differences were observed among nifedipine, labetalol, and hydralazine groups in the present study.To date, ACOG has recommended three types of first-line drugs that can be used as emergency management of hypertension in pregnancy: oral nifedipine, intravenous labetalol, and intravenous hydralazine. The blood pressure targets to be achieved in patients with hypertensive emergencies in pregnancy differ from one guideline to another. It is worth noting that the target for MAP reduction may vary across hospitals. Hence, further processing of these ordinal data was not carried out.Our data suggested that oral nifedipine and intravenous labetalol and hydralazine regimens can be used to treat hypertensive emergencies in pregnancy. If 20-25% reduction of MAP is used as the target, where three doses was set as the maximum, the intravenous hydralazine monotherapy had the lowest failure rate (1 patient). In contrast, intravenous labetalol monotherapy had a failure rate 7 patients . As reported previously, labetalol group had relatively low efficacy and required cross-treatment or alternative treatment. where labetalol and nifedipine had no significant different in reduction of the blood pressure. Rapid reduction of the blood pressure in nifedipine group in our study also similar with previous study where the reduction of the blood pressure was achieved faster by nifedipine compared with hydralazine. Both nifedipine and hydralazine work by resulting vasodilating effects., However, hydralazine has more effect on the arteries than veins while nifedipine, as a calcium channel blocker, causes overall vasodilation, thereby leading to a decrease in peripheral vascular resistance. Taken altogether, nifedipine could be the most efficacious when administered at a single dose.Based on the data of systolic pressure following post-administration time, nifedipine had maximum effectiveness by one dose of administration, but experienced a rebound after 4 hours. As in the labetalol group, the blood pressure reduction peaked twice; at post-20 and -60 minutes administration. Patients in hydralazine group had the lowest blood pressures at three points of measurement: at post-20, -40, and -60 minutes administration. These findings suggest that titration dose is required. Comparative analysis among the three drugs using a single dose yielded a statistical significance of p=0.037. When administered with a single dose, nifedipine performed the best, followed by labetalol and hydralazine and no significant difference of efficacy between labetalol and nifedipine. The result is similar to the finding from a previous studyAccording to the ACOG guidelines, the maximum dose of emergency antihypertension is 3 times administration within 60 minutes. The comparative analysis revealed that hydralazine yielded the most optimum reduction of blood pressure, followed by nifedipine and labetalol, respectively. This could be observed through the significant reduction of blood pressure on the first until the fourth measurements.– Nonetheless, other studies reported the occurrence of nausea and vomiting as adverse effects of labetalol (16%) or nifedipine (8%). In another study, patients in labetalol and nifedipine group experienced dizziness and/or headaches (24% vs 12%), palpitations (8% vs 4%), and foetal heart rate abnormalities (4% vs 8%). These different findings on side effect might be due to the maximum dose used in both foregoing studies, which was 5 doses.,We did not witness any adverse effects experienced by the mothers or infants following the drug administration, in which our data are similar to that of reported.The strengths of this study include the multicentred randomized controlled study design, intensive monitoring, and repeated measurements up to seven times. However, this study is limited by the fact that some of the hospitals only used single blinding because labetalol and hydralazine are new to some doctors. We also did not consider the circadian rhythms in our study and this might affect the blood pressure. Some of the side effects were measured subjectively such as nausea, vomit, dizzy, palpitation, headache and chest pain. However, the methods were exactly the same in all groups.Our data suggested that nifedipine is the most effective in reducing blood pressure using a single dose administration during hypertensive emergency in severe preeclampsia. The lowering blood pressure effect of nifedipine was not significantly different to labetalol but was significantly superior as compared with hydralazine. Nifedipine had a significant rebound phenomenon in blood pressure after four hours of drug administration, hence the necessity of re-administering antihypertensives. In maintaining the low blood pressure, hydralazine was significantly more effective than labetalol and no different effectiveness between hydralazine and nifedipine. All drugs are considered safe after triple dose administration within one hour. Based on the present study, in high resource settings, hydralazine is recommended to treat severe preeclampsia cases with hypertensive emergency since it reduces the blood pressure rapidly and has no rebound phenomenon. We recommend to use nifedipine in the low resource settings since it is cheap and easy to use and store while still has good ability to reduce the blood pressure. However, blood pressure maintenance is required because it might rebound after approximately six hours. Thank you for revision of your manuscript.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?I cannot comment. A qualified statistician is required.Are all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:John Wantania : Maternal Fetal Medicine ;                 Windy Mariane Virenia Wariki :  Clinical EpidemiologistWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Authors addressed all of my comments. The revised manuscript can be accepted for indexing.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, Alternative Medicine, Public Health, BioinformaticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This article is useful, but still there are several weaknesses that need to be considered.The introduction section should describe in more depth what is the novelty and urgency of this study.The methods, and interpretations of the statistical analysis are not carefully presented. Therefore, further consultations with biostatistician or epidemiologist may potentially improve this article.The authors may not be careful enough in writing due to some mistakes in grammar and inconsistency in writing.Thank you for your hard work. As a reviewer, I appreciate the efforts of the authors. The methods and research results presented are excellent and it hoped that great benefits obtained from this article. However, there are still some minor issues to address, which are listed below, in general:Introduction Paragraph 4: The authors mentioned about the recommendations for antihypertension drugs in preeclampsia and stated, “Multiple drugs are included and excluded from the list of drugs of choice for the treatment of severe preeclampsia”. This sentence is a little unclear. Could you please clarify exactly what you mean about multiple drugs being included and also excluded as well? The authors should modify the sentence so that it is easier for the reader to understand. Paragraph 4: In the third sentence the authors explained the dosage form of hydralazine, without writing down the dosage form of labetalol. Paragraph 5: The authors stated: “Hydralazine and labetalol are considered to have a balanced effectiveness and side effect in lowering blood pressure in preeclampsia”, and “Another study comparing nifedipine and labetalol…” Here, the authors should explain if the indicator used to measure “lowering blood pressure” were the same, for example the mean arterial pressure (MAP), and need to confirm quantitatively how much the blood pressure declined so that the reader can judge that they are comparable. Paragraph 6: In the objective of this study, the authors mentioned the dosage form of nifedipine and labetalol. The authors should consistently explain the dosage form of hydralazine as well, bearing in mind that nifedipine and labetalol have different dosage forms.Methods Study setting and registration In line with the subtitle above including registration, the authors should explain matters related to registration in this section instead of explaining it in the ethical considerations section. However, if the authors should explain this in ethical considerations section, can “registration” in this subtitle be eliminated? Patient recruitment and criteria In the second sentence the authors stated “The minimal sample size of the study was 13 patients”. This is different from the explanation in the Results section that the total number of samples was 60. Does it mean that the results of the minimum sample size calculation are 13 patients in each group? The minimum sample calculation formula used by the authors is for two groups. Considering that this research was an unpaired numerical comparative study conducted on three groups with measurements of seven times, it would be more appropriate if the authors calculated the number of samples based on the above considerations. Blinding and study procedure The authors are suggested to explain in more detail about the following sentence “For example, the patient who arrived first and second to the hospital should be given kit no 41 and 23”. Furthermore, the authors also need to describe who are the “health workers” specifically, mentioned in this sentence “Health workers were instructed to administrate one pair of drug….” with reference to Peraturan Menteri Kesehatan Republik Indonesia Nomor 13 Tahun 2020. Endpoints: The authors stated “The blood pressure was measured seven times...” As a suggestion, this sentence should be more suitable when explained in the subtitle “Blinding and study procedure” above. Statistical analysis The authors have explained that a normality test has been carried out, therefore it is advised to write down the name of the normality test used, for example by taking into account the number of samples, or other considerations or assumptions.Results Figure 1: In the last column of the “Analysis” section, it was written that the total number of respondents was 49 patients, quite different from the explanation in the Results section that 60 patients were analyzed. It is suggested that the authors need to be clearer, for example, when and for what to analyzing 60 patients, or only 49 patients. Required time for nifedipine, labetalol, and hydralazine group achieved the MAP The authors have explained that the results regarding the time required for the three drugs to reach the target MAP are presented in Figure 1. However, the results shown in figure 1 are different from this explanation. Nifedipine (page 6) In this section, the author has directed the reader for three times to see the results in Table 2, even though all the data in this section are only showed in table 2. As a suggestion, it would be better if Table 2 was written only once, for example at the beginning or end of a paragraph of the explanation. Sentence stating “Nifedipine decrease the MAP 15.61 mmHg, 5.46 mmHg and 12.00 mmHg 20 min post the first…”. However, 5.46 mmHg and 12.00 mmHg are not found in Table 2. Similar with the sentence sixth which is in Table 2 the p=0.010 and p=0.024 are not found. Table 2 On the footnote of table 2 was written the mean difference is significant at p<0.005. But in this table, there is no p-value less than 0.05 (p<0.05) which means that this mark (*) no need to be mentioned in the footnote. Page 7: The description below Figure 2 where the author wants to explain the changes of mean systolic, diastolic and MAP. The authors are asked to be more careful in presenting the results where the appearance of Figure 2 inconsistent from this explanation. Figure 2 is a comparison of the three types of drugs in achieving MAP. Figure 2: It would be more informative and flowing if the appearance of Figure 2 and its description are in the “Effectiveness comparisons of nifedipine, labetalol, and hydralazine” section compared to the current view which is in the section or explanation of nifedipine.Labetalol The authors are advised to revise the figure number that is not in accordance with the explanation about labetalol, which is different from what is presented in Figure 3.Hydralazine In Table 4, the results of the analysis to explain the decrease in systolic blood pressure were not found. Also, Figure 4 is a description of labetalol, not hydralazine. Page 8: Explanation of the results of Kruskal-Wallis test is not present in the Figure 5, but in Figure 6. Table 7: Suggestion for the authors regarding reported side effects where there was only one namely tachycardia, it would be better if the result is presented in a narrative manner.Discussion Discussion section is still having major problems, addition information requested on strength and limitation are not clearly explain. The authors are lacking in explanation the agreements and disagreements with findings from other studies. Limitations The limitation in methodological should be clearly explained and address as one of the limitations of this study. The authors are suggested to give specific recommendations to the reader as respond to key findings.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?I cannot comment. A qualified statistician is required.Are all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:John Wantania : Maternal Fetal Medicine ;                 Windy Wariki :  Clinical EpidemiologistWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. Thank you for your hard work. As a reviewer, I appreciate the efforts of the authors. The methods and research results presented are excellent and it hoped that great benefits obtained from this article. However, there are still some minor issues to address, which are listed below, in general: This article is useful, but still there are several weaknesses that need to be considered. The introduction section should describe in more depth what is the novelty and urgency of this study. The methods, and interpretations of the statistical analysis are not carefully presented. Therefore, further consultations with biostatistician or epidemiologist may potentially improve this article. The authors may not be careful enough in writing due to some mistakes in grammar and  inconsistency in writing. RESPONSES:  Thank you for reviewing our manuscript. The comments and suggestions have improved the quality of our current manuscript significantly. We have added the required information in the methods as requested. Also, we have corrected some typos in the numbering related to the statistics. We have corrected the labels of the figures. The connection between the figures and the explanation texts have been corrected and checked for the correctness.Introduction Paragraph 4: The authors mentioned about the recommendations for antihypertension drugs in preeclampsia and stated, “Multiple drugs are included and excluded from the list of drugs of choice for the treatment of severe preeclampsia”. This sentence is a little unclear. Could you please clarify exactly what you mean about multiple drugs being included and also excluded as well? The authors should modify the sentence so that it is easier for the reader to understand. RESPONSES:  We have revised the sentence. Paragraph 4: In the third sentence the authors explained the dosage form of hydralazine, without writing down the dosage form of labetalol.Intravenous labetalol and intravenous hydralazine have long been considered as first-line therapy in hypertensive emergencies, severe hypertension in pregnant women, and in the postpartum period”. RESPONSES:  Have been included: “ Paragraph 5: The authors stated: “Hydralazine and labetalol are considered to have a balanced effectiveness and side effect in lowering blood pressure in preeclampsia”, and “Another study comparing nifedipine and labetalol…” Here, the authors should explain if the indicator used to measure “lowering blood pressure” were the same, for example the mean arterial pressure (MAP), and need to confirm quantitatively how much the blood pressure declined so that the reader can judge that they are comparable. RESPONSES:  We have added more detailed of the information related to the studies. Paragraph 6: In the objective of this study, the authors mentioned the dosage form of nifedipine and labetalol. The authors should consistently explain the dosage form of hydralazine as well, bearing in mind that nifedipine and labetalol have different dosage forms. intravenous hydralazine as antihypertensives in severe preeclampsia.” RESPONSES:  Have been included: “Therefore, this study was conducted to compare the effectiveness of oral nifedipine, and intravenous labetalol andMethods Study setting and registration In line with the subtitle above including registration, the authors should explain matters related to registration in this section instead of explaining it in the ethical considerations section. However, if the authors should explain this in ethical considerations section, can “registration” in this subtitle be eliminated? RESPONSES:  Thank you for the suggestion. We have changed the subheading to: “Study setting” only and moved the “registration” into: “Ethical considerations and registration” Patient recruitment and criteria In the second sentence the authors stated “The minimal sample size of the study was 13 patients”. This is different from the explanation in the Results section that the total number of samples was 60. Does it mean that the results of the minimum sample size calculation are 13 patients in each group? RESPONSES: 13 patients are minimal sample size for each group. Therefore, we have revised to: “The minimal sample size of the study was 13 patients for each arm.” The minimum sample calculation formula used by the authors is for two groups. Considering that this research was an unpaired numerical comparative study conducted on three groups with measurements of seven times, it would be more appropriate if the authors calculated the number of samples based on the above considerations. RESPONSES: We have checked again and we confirm that this formula also can be used for three groups. Blinding and study procedure The authors are suggested to explain in more detail about the following sentence “For example, the patient who arrived first and second to the hospital should be given kit no 41 and 23”.   RESPONSES: We have revised the sentence and we believe it is clear now. “For example, if the list from the software run was 41, 23, 4 and soon, the patient who arrived first, second and third to the hospital should be given kit no 41, 23 and 4, respectively.” Furthermore, the authors also need to describe who are the “health workers” specifically, mentioned in this sentence “Health workers were instructed to administrate one pair of drug….” with reference to Peraturan Menteri Kesehatan Republik Indonesia Nomor 13 Tahun 2020. RESPONSES: They were doctors. And the text has been revised: “The enrolment of the patient was conducted by the doctors in each centre. The doctors have been informed about the study and have been trained. The doctors and patients did not know the drugs contained in the kit.” Endpoints: The authors stated “The blood pressure was measured seven times...” As a suggestion, this sentence should be more suitable when explained in the subtitle “Blinding and study procedure” above. RESPONSES:  Thank you for the suggestion. The sentence has been moved within “Blinding and study procedure” subheading. Statistical analysis The authors have explained that a normality test has been carried out, therefore it is advised to write down the name of the normality test used, for example by taking into account the number of samples, or other considerations or assumptions. RESPONSES: We have added the information of the test used to measure the normality of the data. We added: “The normality of data was measured using the Kolmogorov-Smirnov test.”Results Figure 1: In the last column of the “Analysis” section, it was written that the total number of respondents was 49 patients, quite different from the explanation in the Results section that 60 patients were analyzed. It is suggested that the authors need to be clearer, for example, when and for what to analyzing 60 patients, or only 49 patients. RESPONSES: Thank you for questioning this. We have added the information related to this. We add: “Out of 60 patients, 11 patients did not achieve the MAP target after three doses of the tested drugs and therefore were excluded for effectiveness analysis of nifedipine, labetalol, and hydralazine to reduce the blood pressure.” Required time for nifedipine, labetalol, and hydralazine group achieved the MAP The authors have explained that the results regarding the time required for the three drugs to reach the target MAP are presented in Figure 1. However, the results shown in figure 1 are different from this explanation.dose for nifedipine, labetalol, and hydralazine to achieve MAP target” “Data regarding the dose required for nifedipine, labetalol, and hydralazine to reach the target MAP (20% reduction) are presented in Figure 2.” RESPONSES: Thank you pointing this mistake. It should be Figure 2. Also it has been changed to “Required Nifedipine (page 6) In this section, the author has directed the reader for three times to see the results in Table 2, even though all the data in this section are only showed in table 2. As a suggestion, it would be better if Table 2 was written only once, for example at the beginning or end of a paragraph of the explanation. RESPONSES: Now it only mentioned only once in the beginning. Sentence stating “Nifedipine decrease the MAP 15.61 mmHg, 5.46 mmHg and 12.00 mmHg 20 min post the first…”. However, 5.46 mmHg and 12.00 mmHg are not found in Table 2. Similar with the sentence sixth which is in Table 2 the p=0.010 and p=0.024 are not found. RESPONSES:  We appreciated with this correction. We have corrected the sentences: “Nifedipine decreased the MAP 15.61 mmHg, 6.37 mmHg and 2.90 mmHg 20 min post the first, second and the third dose of nifedipine. The MAP reduction on 20 min post the first dose was significant statistically with p<0.001.” Table 2 On the footnote of table 2 was written the mean difference is significant at p<0.005. But in this table, there is no p-value less than 0.05 (p<0.05) which means that this mark (*) no need to be mentioned in the footnote. RESPONSES:  Now the * has been deleted. And ** has been changed to “*The mean difference is significant at p<0.01.” The * in the table also have been deleted. Thank you. Page 7: The description below Figure 2 where the author wants to explain the changes of mean systolic, diastolic and MAP. The authors are asked to be more careful in presenting the results where the appearance of Figure 2 inconsistent from this explanation. Figure 2 is a comparison of the three types of drugs in achieving MAP.Figure 3. The data suggested there was a sharp decrease of systolic and diastolic after the first dose of nifedipine and the blood pressure kept decrease until 20 min after the third dose (after 2 hours of first dose) but it started to bounce again afterward .” RESPONSES: Thank you for catch this mistake. We realized that there was a shift of the labels of the figures. This should be Figure 3 not Figure 2. Now it has been corrected into Figure 3. The revised texts: “The changes of the mean systolic, diastolic and MAP are presented in Figure 2: It would be more informative and flowing if the appearance of Figure 2 and its description are in the “Effectiveness comparisons of nifedipine, labetalol, and hydralazine” section compared to the current view which is in the section or explanation of nifedipine. RESPONSES: We agree with this suggestion because it is hard to follow the texts and the Figure 2. We have re-requested the layout editor to move Figure 2 directly under the subheading: “Required dose for nifedipine, labetalol, and hydralazine to achieve MAP target”.Labetalol The authors are advised to revise the figure number that is not in accordance with the explanation about labetalol, which is different from what is presented in Figure 3. RESPONSES: As we responded previously, we realized that there was a shift of the labels of the figures. Now all have been corrected.Hydralazine In Table 4, the results of the analysis to explain the decrease in systolic blood pressure were not found. Also, Figure 4 is a description of labetalol, not hydralazine.c Analysed using Friedmann test.”  RESPONSES: The systolic data was not distributed normally and therefore the Friedmann test and this analysis produced one p-value only and no 95%CI. To ensure this is clear, we have included the information as a note under the Table 4. “ As we stated previously, all labels of the figures have been rechecked and corrected. Page 8: Explanation of the results of Kruskal-Wallis test is not present in the Figure 5, but in Figure 6. RESPONSES: All labels of the figures have been rechecked and corrected. Table 7: Suggestion for the authors regarding reported side effects where there was only one namely tachycardia, it would be better if the result is presented in a narrative manner. RESPONSES: Now Table 7 has been deleted as suggested and we have added “side effects” after the secondary outcome.Discussion Discussion section is still having major problems, addition information requested on strength and limitation are not clearly explain. RESPONSES: We have provided the information related to the strengths and limitations of the study. The authors are lacking in explanation the agreements and disagreements with findings from other studies. RESPONSES: Thank you for your suggestions. Unfortunately, available studies are limited and therefore it is not possible to compare with previous studies. Limitations The limitation in methodological should be clearly explained and address as one of the limitations of this study. The authors are suggested to give specific recommendations to the reader as respond to key findings. RESPONSES:  We have listed all the limitations of the study. We also have added specific recommendation from the results of the study. We added: “ Based on the present study, in high resource settings, hydralazine is recommended to treat severe preeclampsia cases with hypertensive emergency since it reduces the blood pressure rapidly and has no rebound phenomenon. We recommend to use nifedipine in the low resource settings since it is cheap and easy to use and store while still has good ability to reduce the blood pressure. However, blood pressure maintenance is required because it might rebound after approximately six hours.” The study was well-designed and conducted with balanced conclusions.The title of the study is clear and balanced however the information on RCT is needed such as: “Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia: a randomized control trial”.The structured abstract contains all important information, including the registry number.The introduction section provides the importance and significance of the problem as well as the scientific gap. The aim of the study is also clearly stated. The study setting is clearly stated although the justification for choosing those hospitals might be helpful.The sample size is relatively small, but the justification and calculation are provided on how the sample was calculated.Double blinding and randomization were conducted to avoid bias.The procedures are explained adequately but the information on whether the healthcare workers received the training from the researchers is important to ensure that they worked following the guideline.The Results assisted with a flowchart, and this helps the readers to understand each step of enrolment, allocation, follow-up, and analysis.The baseline of the data of the patients between the group are relatively homogeneous.The comparations between drugs were conducted for each endpoint and should be appreciated.Table 7. The information in this table can basically be written in two sentences only since there were no side effects in the labetalol and hydralazine groups. Also “Secondary outcome” could be changed to “Side effect.”Discussion and conclusion are balanced; the study's strengths and limitations are discussed. However, some suggestions to measure soluble fms-like tyrosine kinase 1, endothelin-1, and soluble endoglin likely do not support the data of this study.The study assessed the effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia (SP). SP is a significantly important health problem in both developed and developing countries. My comments:Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, Alternative Medicine, Public Health, BioinformaticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The study assessed the effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia (SP). SP is a significantly important health problem in both developed and developing countries. My comments: The study was well-designed and conducted with balanced conclusions. RESPONSES: Thank you for your appreciation. The title of the study is clear and balanced however the information on RCT is needed such as: “Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia: a randomized control trial”. RESPONSES: We have revised the tittle by adding: “: a randomized control trial” The structured abstract contains all important information, including the registry number. The introduction section provides the importance and significance of the problem as well as the scientific gap. The aim of the study is also clearly stated.  RESPONSES: Thank you for your appreciation. The study setting is clearly stated although the justification for choosing those hospitals might be helpful. RESPONSES: The reasons have been provided: “These hospitals were chosen because they are affiliated with Faculty of Medicine, Universitas Riau.” The sample size is relatively small, but the justification and calculation are provided on how the sample was calculated. Double blinding and randomization were conducted to avoid bias. RESPONSES: Thank you for your appreciation. The procedures are explained adequately but the information on whether the healthcare workers received the training from the researchers is important to ensure that they worked following the guideline. RESPONSES: We have added the information that the healthcare workers have been trained: “The doctors have been informed about the study and have been trained.”  The Results assisted with a flowchart, and this helps the readers to understand each step of enrolment, allocation, follow-up, and analysis. The baseline of the data of the patients between the group are relatively homogeneous. The comparations between drugs were conducted for each endpoint and should be appreciated RESPONSES: Thank you for your appreciation. Table 7. The information in this table can basically be written in two sentences only since there were no side effects in the labetalol and hydralazine groups. Also “Secondary outcome” could be changed to “Side effect.” RESPONSES: Thank you for the suggestion. Now Table 7 has been deleted and we have added “side effects” after the secondary outcome. Discussion and conclusion are balanced; the study's strengths and limitations are discussed. However, some suggestions to measure soluble fms-like tyrosine kinase 1, endothelin-1, and soluble endoglin likely do not support the data of this study. RESPONSE:  Thank you for the suggestion. This sentence has been deleted.


History of chronic kidney disease and kidney transplantation is known to influence physical performance capacity. The aim of this study was to compare the physical performance of pediatric kidney transplant recipients to healthy controls and to find possible correlations between clinical parameters and physical performance capacity.Twenty-four pediatric kidney transplant recipients (62.5% boys) were tested at a median age of 10.8 years. Physical performance capacity was tested with a test set including six different components assessing muscle endurance, strength, speed, and flexibility. The control group consisted of 273 healthy age-matched schoolchildren. Clinical parameters were collected as part of routine follow-up protocol. The majority of patients (62.5%) had congenital nephrotic syndrome of Finnish type (CNS) as primary diagnosis, and therefore, the results of CNS recipients were compared to the other disease groups.The physical performance capacity in pediatric kidney transplant recipients was lower compared to healthy controls. Surprisingly, no statistically significant correlation was found between graft function and physical performance capacity. The CNS patients scored worse than patients with other diagnoses in all test domains except for sit-and-reach and shuttle run, but the differences did not reach statistical significance.The physical performance of pediatric kidney transplant recipients is reduced, especially in those with congenital nephrotic syndrome. Clinical parameters, including graft function, did not predict physical performance capacity, suggesting that the reduced physical performance seems to be of multivariable cause.The online version contains supplementary material available at 10.1007/s00467-022-05758-0. Kidney transplantation has become the preferred treatment in pediatric severe chronic kidney disease (CKD). With 10-year patient survival rate exceeding 90% [We, among others, have shown that the physical performance of pediatric patients with a history of solid organ transplantation is decreased . Muscle Exercise capacity and its associations with clinical parameters after kidney transplantation are of clinical interest. In pediatric recipients, no correlations have been found between dialysis duration, time since transplantation, kidney function estimated by glomerular filtration rate (GFR), BMI, blood pressure medication, hematocrit or serum phosphorus levels, and exercise capacity –13. TherApproximately 40% of pediatric kidney transplants in Finland are performed for patients with congenital nephrosis of the Finnish type (CNF). Long-lasting hypoproteinemia before nephrectomy is known to lead to muscle hypotonia. We therefore compared physical performance between CNS patients and other kidney transplant recipients to see whether there are any differences between the two groups. We hypothesized that physical performance would be inferior in pediatric kidney transplant recipients when compared to controls, as previously stated . We alson = 3), recent transplantation (n = 1), and recent scoliosis operation (n = 1)). In addition, 12 recipients did not participate in the study due to other reasons, such as scheduling or logistic problems. This study cohort included 19 recipients from our previous study [All pediatric kidney transplants in Finland are performed at the study center and the recipients are followed up at our unit at least yearly. We enrolled recipients to the study during their annual follow-up visit with the following inclusion criteria: (1) history of kidney transplantation, 2) age 10–12 years, and (3) capability to perform the tests used. A total of 41 eligible recipients were identified; 5 of them were excluded because of medical reasons (neurology ( age 10–1n = 5), congenital nephrotic syndrome of the Finnish type (CNS) (n = 15), and acquired diseases, including hemolytic uremic syndrome, acute kidney injury, CKD unspecified, and congenital kidney failure (n = 4).Finally, 24/41 (58.5%) of the eligible recipients were enrolled between November 2016 and July 2021, including one child aged 8.1 and another aged 13.4 years, since they were already tested, to increase the number of recipients in the study. The pre-transplant diagnoses were as follows: congenital anomalies of the kidney and the urinary tract (CAKUT)  at school, and this was described in medical records.Physical performance was evaluated using a standardized test set, which has been described in our recent study , as wellThe key clinical data of the recipients were obtained from medical reports. These test results were obtained simultaneously with the physical performance testing. The data included a wide range of laboratory results, height, weight, and systolic and diastolic blood pressure. These data were measured as part of the routine follow-up protocol. The neurological and psychological status of all the recipients was obtained retrospectively from the records and labeled as normal/deviant. All recipients were evaluated by a pediatric neurologist and psychiatrist as per the routine pre-transplant protocol and followed up according to the results. All recipients underwent a neuropsychological evaluation at preschool age. Early motor development was obtained from physiotherapy records and labeled as normal/deviant/delayed regarding the achievement of early motor milestones. All patients received triple-drug immunosuppression including calcineurin inhibitor (ciclosporin A or tacrolimus), antimetabolite (azathioprine or mycophenolate), and methylprednisolone. Rejections were detected either at protocol or indication biopsies and classified according to the Banff classification . LaboratOffice and ambulatory blood pressures (BP) were measured during each annual follow-up visit or at a preceding outpatient visit within 3 months of the physical performance test. Office BP was measured repeatedly at minimum three times and ambulatory BP was by an oscillometric monitor  or Schiller BR-102 Plus . BP was categorized as normal if below the 90th percentile and hypertensive if equal to or above the 95th percentile . Forty-sU-test and correlations were analyzed with Spearman’s correlation coefficient.All statistical analyses were performed using IBM SPSS Statistics 27 . The results are presented as mean (SD) or median (range) or number of recipients (%), as appropriate. Comparisons of the groups were performed with the Mann–Whitney All physical test results were indexed to remove the effect of age or gender. The indexes were calculated by dividing the physical test results with the mean result of control children by age and gender. A physical performance capacity total score was calculated by adding together all indexed scores of an individual’s results, except for shuttle run due to the relatively large number of missing performances.p = 0.02) and their BMI was lower  compared to the other recipients at the time of the study. Patients with CNS more often had peritoneal dialysis as treatment modality (p = 0.05) compared to patients with other diagnoses. The duration of dialysis did not, however, differ significantly between the diagnosis groups (p = 0.60). We found no significant differences in any other recipient characteristics.The median age at the time of the study was 10.8 (8.1–13.4) years. The median age at the time of the transplantation was 1.5 (1.0–13.2) years and the minimal time since transplantation was 2.6 months. There were more males (62.5%) than females in the study cohort (Table p = 0.03) and weighed more  than the recipients. The controls performed better than the recipients in all test domains except in sit-and-reach test. In leg lift test, sit-and-reach test and shuttle run test the controls achieved indexed mean results of the age group.The median age at testing was 11.0 (8.0–13.0) years. The controls were taller  (Table p = 0.04), diastolic blood pressure and sit-up test , P-Mg and back extension , potassium and sit-up , dialysis duration and leg lift , neurology and leg lift , repeated squatting , and shuttle run  and fasting plasma glucose (FPG) and shuttle run  (Table p = 0.5) or BMI  did not correlate with physical activity in this cohort  and Physical Performance Total Score 0.42, 4) Table , height 2, 4 TablAll the kidney transplant recipients and controls attended school PE, and 18/24 recipients (75%) participated in a sports hobby at least once a week. Indexed physical performance test results of 24 pediatric kidney transplant recipients were compared between the transplant recipients attending only physical exercise (PE) at school and those attending PE and having at least one sports hobby per week. We did not find any significant difference in the test results according to self-reported physical activity.n = 15) and other primary diagnosis (n = 9). There was no significant difference between the groups, although the recipients with other diagnoses than CNS seemed to perform better in all test domains except for sit-and-reach and shuttle run. Children with CNS had a physical performance capacity of 4.13 (0.79) versus children with other CKD as primary diagnosis 4.48 (0.90), p = 0.174. Four recipients (26.6%) with CNS were identified as having delayed motor development during early childhood, which was resolved during the follow-up. When correlations of neurologic development and Physical Performance Total Capacity were examined, the correlations were not significant, but when a subgroup of early motor developmental delay was taken into account, the correlation with neurologic development and Physical Performance Total Capacity became significant .Indexed physical test results of 24 pediatric kidney transplant recipients were divided in two diagnostic main groups: patients with congenital nephrosis . This could promote physical activity compared to recipients with non-transplanted CKD and therefore promote the achievement of motor skill milestones and better physical performance at older age. On the contrary, Wolf et al. [In our study cohort, patients with congenital nephrotic syndrome tended to perform worse than patients with other primary kidney disease. The difference between the groups was seen especially in tests measuring core muscle strength, i.e., sit-up and back extension, although the difference did not reach statistical significance. Similar findings of reduced core muscle strength were seen in our previous study concerning all pediatric solid organ transplant groups , which rf et al.  found thImproving physical activity after pediatric kidney transplant and therefore promoting functional capacity and quality of life is important in improving the long-term outcomes of pediatric kidney transplant recipients. A Norwegian study reported that increasing early physiotherapy and follow-up of physical activity after pediatric kidney transplant had a significant positive impact on the cardiorespiratory fitness, quality of life, and mental health of pediatric kidney transplant recipients . Then agDespite being a nationwide study, the study sample remains small. This may have an impact on the study results. There is also an apparent limitation with interpreting the results of the shuttle run test, since problems with slipperiness of the floor prevented performing the test for a significant subset of patients 7/24). The slipperiness was a surprising problem with the floor material, even though the floor material in the physiotherapy unit should be suitable for physical performance testing. The problem could not be solved with indoor shoes or going barefoot. As for the clinical parameters and their associations with physical performance, some of the clinical parameters, such as GFR, hemoglobin, and infection markers, were at relatively good level in all study subjects, which might also have influenced our results Supplementary file1 (DOCX 29.4 KB)Below is the link to the electronic supplementary material.


What are the long-term outcomes for hospitalized patients with reduced kidney function on admission who are discharged with apparently normal kidney function?In this cohort study that included 40 558 adults, patients with reduced kidney function on admission who were discharged with apparently normal kidney function experienced 18% increased mortality in the year following the hospitalization. The risk of end-stage kidney disease increased by 267% in the 10 years following the hospitalization.The findings of this study suggest that reversible reduction in kidney function among hospitalized patients is associated with an increased long-term risk for end-stage kidney disease and mortality. Acute kidney injury is associated with poor outcomes, but the clinical implication of reversible serum creatinine level fluctuations during hospitalization not necessarily defined as acute kidney injury is poorly understood.To investigate the long-term outcomes of patients without previously diagnosed kidney disease who present with decreased kidney function and are subsequently discharged with apparently normal kidney function.2. Patients with preexisting chronic kidney disease were excluded.A retrospective cohort study was conducted of patients hospitalized in a large tertiary hospital in Israel between September 1, 2007, and July 31, 2022. The study included patients admitted to an internal medicine ward. Patients had not undergone dialysis during the index hospitalization, had at least 3 creatinine tests performed during hospitalization, and had a discharge estimated glomerular filtration rate (eGFR) exceeding 60 mL/min/1.73 m2 was regarded as normal. Exposure was defined based on the association between the first and last values determined during hospitalization.Glomerular filtration rate was estimated from serum creatinine values using the updated 2022 Chronic Kidney Disease Epidemiology Collaboration formula, and eGFR greater than 60 mL/min/1.73 mAll-cause mortality in the year following the index hospitalization and end-stage kidney disease (ESKD) in the 10 years following the index hospitalization.2.A total of 40 558 patients were included. Median age was 69  years, with 18 004 women (44%) and 22 554 men (56%). A total of 34 332 patients (85%) were admitted with a normal eGFR and 6226 (15%) with decreased eGFR. Patients with decreased eGFR on presentation had an 18% increased mortality in the year following hospitalization  and a 267% increased risk of ESKD in the 10 years following hospitalization , despite having been discharged with apparently normal kidney function. The highest risk was noted in patients who presented to the hospital with an eGFR of 0 to 45 mL/min/1.73 mThe findings of this cohort study suggest that patients who present with decreased kidney function and are discharged without clinically evident residual kidney disease may be at increased long-term risk for ESKD and mortality. This cohort study evaluates 1- and 10-year mortality of patients with decreased estimated glomerular filtration rate on admission whose kidney function appeared to have returned to normal at discharge. In this analysis, an increase of more than 0.1 mg/dL per day in serum creatinine levels increased mortality risk, whereas stable or decreasing creatinine levels were associated with reduced risk.Indeed, worsening kidney function was also noted to be a predictor of increased mortality, even when not meeting the definition of AKI.16 and were subsequently discharged from the hospital with apparently normal kidney function.However, the clinical implication of creatinine level changes, which are not necessarily defined as AKI, with subsequent full recovery, is poorly described. This study aimed to investigate the long-term outcome of patients without previously diagnosed kidney disease who presented with decreased kidney function but may not have met the full AKI criteriaSTROBE) reporting guideline. Patients included in the study were those admitted to an internal medicine ward in SMC between September 1, 2007, and July 31, 2022, were older than 18 years at hospitalization, were hospitalized between 2 and 14 days, had not undergone dialysis during the index hospitalization, and had at least 3 creatinine tests performed during their hospitalization. Although our primary analysis focused on the first and last creatinine values, by mandating 3 or more creatinine level determinations, we indirectly ensured sufficient monitoring of kidney function during the patients’ hospitalizations. For patients admitted multiple times during the study period, only the first hospitalization was retained.This was a retrospective cohort study based on the integration of the electronic medical records from Sheba Medical Center (SMC) with Israeli nationwide records regarding end-stage kidney disease (ESKD) using TIMNA, a national research platform established by the Israeli government for conducting big-data research and combining deidentified health data from multiple health organizations. All medical data generated by SMC are recorded in electronic medical records and subsequently stored in an analytic data warehouse for further study. By a directive in the national health care insurance law, data regarding all patients in Israel with ESKD  are collected in a central registry maintained by the Ministry of Health. These data are manually verified and constantly updated. The mortality status of patients was identified using the official death records maintained by the Ministry of Interior in the State of Israel, which provides comprehensive and up-to-date information on all deaths occurring within the country. The study was approved by the SMC Institutional Review Board and was exempt from the requirement for informed consent due to the use of deidentified data. The reporting of this study aligns with the Strengthening the Reporting of Observational Studies in Epidemiology (17 Only patients with discharge estimated GFR (eGFR) values over 60 mL/min/1.73 m2 were included.Glomerular filtration rate (GFR) was estimated from creatinine values using the Chronic Kidney Disease Epidemiology Collaboration formula, updated for the year 2022.International Statistical Classification of Diseases and Related Health Problems: Alphabetical Index codes18 and diagnosis-free text  and patients with admission creatinine levels below the normal limit, both with normal creatinine levels on discharge. To ensure sufficient kidney function changes, we still required at least a 15% improvement in creatinine levels for the low-to-normal group.The study population was described in terms of sociodemographic variables, physical measurements, and background medical conditions. Appropriate statistical tests were selected for each variable. Crude survival curves for each outcome were calculated using the Kaplan-Meier estimator, stratified by the exposure, and compared using the log-rank test.Cox proportional hazards regression was used to estimate the hazard ratio (HR) for each outcome between the 2 exposure groups over the study period, adjusted for the aforementioned variables. The assumption of proportionality of hazards was checked using Schoenfeld residuals.P < .05, was unpaired and 2-sided.Missing data, which are rare in the SMC database for the variables used in this study, were handled using a complete case analysis. The analysis was performed using the R statistical software, version 4.1.2 . The significance threshold, set at Following the application of the eligibility criteria, 40 558 individuals were included in the study; of these, 34 332 (85%) belonged to the normal-to-normal group and 6226 (15%) to the low-to-normal group. A total of 765 patients were excluded due to not meeting the 15% or more increase in eGFR from the initial value required for inclusion in the low-to-normal category. The median age was 69  years, with 18 004 women (44%) and 22 554 men (56%). Patients in the low-to-normal group were older; had a higher prevalence of comorbid conditions, such as diabetes, ischemic heart disease, heart failure, chronic obstructive pulmonary disease, hypertension, and atrial fibrillation; and were more likely to be treated with diuretics or renin-angiotensin-aldosterone system inhibitors on admission and discharge . A totalCrude analysis showed increased mortality in the year following the index hospitalization A and inc2 on admission  than for patients with an eGFR of 45 to 60 mL/min/1.73 m2 .For the mortality outcome in the full study population and within subgroups a dose-response association was evident, with worse outcomes for patients whose admission eGFR was lower . In the 2, we did not find an association between the exposure group and 1-year mortality  and did not have enough data to analyze the risk for 10-year ESKD.Further adjustment for discharge eGFR did not substantially alter the estimates . A 209% increased risk for ESKD was found for patients with admission creatinine levels above the normal limit that subsequently decreased upon discharge compared with patients with admission and discharge normal creatinine levels .2, noted a higher risk of mortality and ESKD among participants with decreased eGFR on admission that was not necessarily confined to the KDIGO definition of AKI11 compared with participants who presented with a normal eGFR. Our findings remained consistent when defining the exposure solely based on creatinine levels. The risk seemed to be graded, with the highest risk for mortality noted in patients who presented to the hospital with an eGFR of less than 45 mL/min/1.73 m2 than with an eGFR of 45 to 60 mL/min/1.73 m2. This increased risk persisted after adjusting for confounders; stratifying by age groups, sex, background disease, and treatment with either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; and when allowing a different baseline HR across age groups. It was not altered by adjusting for discharge eGFR, and we did not observe temporal trends. These results suggest that patients who present with decreased kidney function and are discharged without clinically evident residual kidney disease are at increased long-term risk of ESKD.This study of a large cohort of hospitalized patients discharged with an apparently normal eGFR, defined as eGFR greater than or equal to 60 mL/min/1.73 m16 emphasizing the serious outcomes often associated with acute hospital admissions in cohorts with these demographic characteristics.The high 1-year mortality rate observed in our study reflects the patient cohort, which primarily consists of older individuals with acute or complex conditions. Similar trends have been noted in other studies, such as that by Fløjstrup et al,22 Bucaloiu et al20 found an increased mortality risk and future CKD following an in-hospital reversible AKI among 1610 patients without preexisting kidney disease. Similar findings were found in other studies, with a consistent association between reversible AKI and subsequent clinical outcomes, including subsequent CKD and mortality rate.23 However, kidney outcomes and mortality risk following any reduction in GFR with subsequent full recovery were not studied. Moreover, current guidelines do not recommend long-term follow-up of patients with non-AKI.11 To our knowledge, this is the first study to investigate the mortality risk and ESKD among a large cohort of patients discharged from the hospital with apparently recovered kidney function following any eGFR reduction and without necessarily meeting time-dependent creatinine level–based KDIGO-defined AKI.The association between recovered kidney injury and long-term clinical outcomes was previously described.24 Despite this shortcoming, the use of creatinine level–based eGFR has distinct advantages compared with current risk stratification strategies, which focus on the presence of AKI and an increase in serum creatinine levels over time.27 First, reliance on the definition of AKI may fail to recognize clinical outcomes of patients with smaller serum creatinine increases or variable creatinine level fluctuations. Second, these approaches still require information on baseline serum creatinine levels, which is not always available. In addition, efforts to estimate baseline creatinine levels from in-hospital creatinine tests or by using other patient-based equations were inaccurate and resulted in misclassifications of AKI.28Creatinine level–based eGFR may not accurately reflect the severity of the kidney injury in the acute setting, as creatinine levels are often not increased until several days after AKI has occurred.29 Even though kidney function may seem to be recovered at discharge, the persistent reduction in kidney reserve could have long-term implications. Setting the threshold for normal kidney function at an eGFR of 90 mL/min/1.73 m2 revealed no associations with 1-year mortality, implying that more substantial kidney damage may be required to influence long-term outcomes.A possible explanation for our findings is that an observed decrease in kidney function during hospitalization might reveal an existing decreased kidney reserve, unmasked by the stress of acute illness.Our study has several limitations. We did not have access to the baseline prehospitalization serum creatinine levels of the patients included in our study and therefore cannot definitively establish a full recovery to baseline eGFR. We included only patients with 3 or more creatinine tests during hospitalization, which could result in selectively including patients admitted for more severe medical conditions requiring serial blood testing. We included a heterogeneous hospitalized population with different admission diagnoses and etiologies for reduced kidney function on presentation. We only considered a single hospitalization per patient, because evaluating further hospitalizations was beyond the scope of our study and limited by our lack of access to patient data from other medical institutions.30 First, it is possible that creatinine levels have not yet reached their steady-state peak at the time of measurement, leading to some participants with low-to-normal kidney function being misclassified as having normal-to-normal kidney function. However, such misclassification would likely result in an underestimation of the long-term risks for ESKD and mortality in the low-to-normal group in our findings. Second, Prowle et al19 described a decrease in discharge serum creatinine levels among patients hospitalized in intensive care units, attributed by the authors to a decrease in muscle mass over time during critical illness. This could have potentially misclassified some patients with low to normal eGFR as having normal to normal eGFR. However, the patient population in our study had a substantially shorter hospital stay than those in the Prowle et al study, and a subgroup analysis of patients hospitalized for less than 5 days showed consistent results, limiting the potential for extensive muscle mass loss. The inclusion criteria for the low-to-normal group of at least a 15% eGFR improvement and the additional analysis of patients with more than 30% eGFR improvement indicated substantial creatinine level change unlikely due to critical illness alone. Here again, an underestimation of discharge creatinine levels due to factors other than recovery reinforces our conclusions about the need for long-term follow-up for these patients. In addition, our study could have encountered potential misclassification by including patients with CKD. However, CKD is conventionally indicated by an eGFR of less than 60 mL/min/1.73 m2 for a period exceeding 3 months and has implications for health, as per the KDIGO guidelines.31 By selectively including patients with restored normal eGFR at discharge and excluding those with a previous CKD diagnosis recorded by the admitting physician, this risk is mitigated.The main challenge to the robustness of our results could be the potential misclassification of exposure groups. Relying on creatinine levels to estimate GFR values may not perfectly represent the measured GFR on an individual level and could result in misclassification by several mechanisms.The findings of this cohort study suggest that, in hospitalized patients discharged with apparently recovered kidney function, a decreased eGFR on presentation may be associated with increased mortality in the year following the hospitalization and increased risk of ESKD in the 10 years following the hospitalization. Currently, these populations are not considered at risk unless AKI, as defined by KDIGO, was observed. Therefore, these patients should be advised to continue medical observation following their discharge from the hospital.