|Year : 2014 | Volume
| Issue : 1 | Page : 18-23
Assessment of clinical outcomes and prescribing behavior among inpatients with severe preeclampsia and eclampsia: An Indian experience
Shefalika Kumar1, Dipika Bansal2, Debasish Hota3, Madhu Jain4, Pawan Singh3, BL Pandey1
1 Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Pharmacy Practice, Clinical Research Unit, National Institute of Pharmaceutical Education and Research, Mohali, India
3 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Obstetrics and Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||31-Oct-2012|
|Date of Decision||23-Apr-2013|
|Date of Acceptance||21-Nov-2013|
|Date of Web Publication||16-Jan-2014|
Department of Pharmacy Practice, Clinical Research Unit, National Institute of Pharmaceutical Education and Research, Mohali
Source of Support: None, Conflict of Interest: None
Objectives: The study aims to evaluate the management, maternal-fetal outcomes, and prescription behavior among inpatients with severe preeclampsia and eclampsia.
Materials and Methods: This prospective cohort study in a tertiary referral center was conducted in 164 inpatient pregnant women who fulfilled the inclusion criteria. The study was conducted between November 2005 and February 2007. The patients were followed-up till delivery. Antepartum and intrapartum care and maternal and perinatal outcome were noted. Chief outcome measures were maternal and perinatal mortality and drug use indicators.
Results: Median age at delivery of the women was 25 (22-28) years. Majority were suffering from antepartum eclampsia (52.5%), followed by preeclampsia (31%) and postpartum eclampsia (16.5%). Nulliparity (61.6%) was more common in eclampsia, while multiparity in preclamptic group. A total of 48% had preterm delivery. Most presented with headache (50%) and hyperreflexia (29%). Only 15% presented with all three prodromal symptoms and 86% had hypertension. There was increased morbidity, operative intervention, and admission to intensive care unit. Most babies (67%) weighed <2.5 kg and had poor outcome. The maternal mortality was 0.4/1000. Average number of drugs prescribed in patients of preeclampsia, antepartum eclampsia, and postpartum eclampsia were 13.2, 14.9, and 14.2, respectively. Antibiotics (24.6%) were the most common class of the drugs prescribed in all the groups, followed by vitamin and calcium supplements (22.7%) and antihypertensives (13.5%). Most common antihypertensive used were calcium channel blockers and anticonvulsant magnesium sulphate.
Conclusions: There was increased maternal and perinatal morbidity. Protocols for the management of eclampsia, including antihypertensive and anticonvulsant therapies, should be available and reviewed regularly to improve the standard of care and reduce the prevalence of this dangerous condition.
Keywords: Eclampsia, hypertension, magnesium sulphate, preeclampsia, pregnancy
|How to cite this article:|
Kumar S, Bansal D, Hota D, Jain M, Singh P, Pandey B L. Assessment of clinical outcomes and prescribing behavior among inpatients with severe preeclampsia and eclampsia: An Indian experience. Indian J Pharmacol 2014;46:18-23
|How to cite this URL:|
Kumar S, Bansal D, Hota D, Jain M, Singh P, Pandey B L. Assessment of clinical outcomes and prescribing behavior among inpatients with severe preeclampsia and eclampsia: An Indian experience. Indian J Pharmacol [serial online] 2014 [cited 2020 Nov 23];46:18-23. Available from: https://www.ijp-online.com/text.asp?2014/46/1/18/125159
| » Introduction|| |
Hypertensive disorders complicate 7% -9% of all pregnancies.  The incidence of these disorders in pregnancy is likely to rise with the rising prevalence of obesity.  Hypertensive disorder is the leading cause of maternal mortality in India, accounting for more than 8% of maternal deaths.  The identification and effective management of this entity play a significant role in both maternal and fetal outcome.  It has been estimated that infants born to women with preexisting or gestational hypertension have a 16% risk of perinatal death or serious morbidity and with 36% of them needing "high-level" neonatal care. 
Pharmacotherapy in pregnancy represents a special concern because of the potential risk of teratogenicity and the altered physiological state of the mother.  Up to 10% of congenital anomalies may be ascribed to exposure to medications, alcohol, or other exogenous factors that have adverse effects on the developing embryo or fetus.  The rising use of drugs during pregnancy supports the importance of expanding the evidence about the risks and benefits of drug use during pregnancy and also suggests the need for systems to safeguard prescribing practices for women of reproductive age. Despite the publication of a number of guidelines regarding proper drug use in hypertensive pregnancies,  it is not possible to uniformly implement these because of patient specific disease states, the resident doctor's learning curve, and the physician's medication preferences. Thus, the process of diagnosis and providing optimal pharmacotherapeutic strategy becomes quite complex.  Although the World Health Organization has developed the drug use indicators for evaluating drug use patterns in a region or facility, these are general indicators that do not refer to particular health problem and neither led directly to particular focused interventions required. 
A thorough literature search could not reveal any data on drug usage in complicated pregnancies and its outcome in the Indian scenario. The primary objective of the present study was to assess the quality of health care in severe preeclampsia and eclampsia in context to the Indian health care setting. The secondary objective of this study was to evaluate the dynamics of prescribing behavior in this health disorder.
| » Materials and Methods|| |
This prospective cohort study was conducted in the Obstetrics and Gynecological department of Sir Sundar Lal (SSL) Hospital of Institute of Medical Sciences, Banaras Hindu University, Varanasi, which is a large Indian city having a population more than 4 millions. SSL hospital is a large tertiary care hospital funded by the government and most of the services here are provided free of cost. Majority of the women belong to the lower socioeconomic class. All gravid women with severe preeclampsia and eclampsia admitted to the obstetrics unit between November 2005 and February 2007 were included as ''encounters'' and followed for the entire duration of their hospital stay. Only inpatients were included in the study. A total of 164 women were recruited during the entire study period. The plan of the study was approved by the institute's ethics committee and written informed consent was obtained from all women before participation in the study.
Detailed information regarding clinical features, antepartum and intrapartum care, eclamptic episode, and the maternal and perinatal outcome was sought by analysis of the inpatient case sheets, patient interviews, obstetrician, and the nursing staff. The gestational age at the time of the eclamptic fit was recorded. In postpartum eclampsia, this was taken to be the gestational age at delivery. Maternal morbidity was defined as women having at least one complication of eclampsia or as a result of the management of eclampsia. When the seizures occurred more than once, it was termed as recurrent seizures.
Severe preeclampsia was defined by blood pressure readings higher than 160/110 mm Hg and >5 g of proteinuria in a 24-h urine collection or > 3+ urine dipstick testing of two random urine samples. Eclampsia was defined as presence of new onset seizures in a woman with preeclampsia [American College of Obstetrics and Gynaecology (ACOG)]. 
The treatment guidelines recommended by the National High Blood Pressure Education Program (NHBPEP) Working Group Report  and the ACOG Guideline  are taken into consideration for the management of severe preeclampsia/eclampsia. The evidence gained by the Magpie Trial and the Collaborative Eclampsia Trial ,, was used as standards against which the drug use was measured. Drugs used by the women each day were entered into a predesigned case record form. Drugs were classified into different classes and their individual generic types. Drugs were also classified according to the indications for which they were given. Numbers of drugs prescribed to each patient during the entire duration of hospital stay were calculated.
Statistical analysis was performed using SPSS version 12. Values are expressed as mean with standard deviation, median with interquartile range, numbers, and as percentages. Baseline parameters were compared by Student's paired or unpaired t-test for continuous variables and chi-square or Fisher's exact test was used for categorical variables. P value <0.05 was regarded as significant. Kaplan-Meir survival curve was plotted to assess the gestational age at time of diagnosis. Log rank test was used to compare the curves.
| » Results|| |
During the study period of 14 months, 198 admissions related to hypertensive disorders of pregnancy were recorded. Patient disposition in the study is summarized following the strengthening and the reporting of observational studies in epidemiology (STROBE) in [Figure 1] and their demographic and clinical characteristics in [Table 1]. The median age at delivery of the 164 women included in the study was 25 (22-28). Majority of the cases were antepartum eclampsia 86 (52.5%), followed by preeclampsia 51(31%) and postpartum eclampsia 27(16.5%). Nulliparous status (62%) was significantly more common in eclampsia group (<0.001), while multiparous women (59%) were commoner in preeclamptic group [Table 1]. The gestational age at the time of diagnosis in three groups is presented in [Figure 2].
|Table 1: Demographic, clinical features, and outcome of women with severe preeclampsia and eclampsia|
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|Figure 1: Patient flow diagram (STROBE): Assessment of clinical outcomes and prescribing behaviour in preeclampsia and eclampsia|
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|Figure 2: Kaplan-Meir curves to show probability of diagnosis of severe preeclampsia/eclamptic episode (antepartum and intrapartum seizures) or delivery (postpartum seizures) at different gestational ages|
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Clinical Features and Outcome
The clinical features, maternal and perinatal outcome are summarized in [Table 1]. Headache was most common symptom in both preeclampsia and eclampsia group (41.2% vs. 54.9%, P = 0.073), while most common sign was oedema in preeclampsia (65% vs. 37%, P = 0.001) and hyperreflexia in eclampsia group (42%). Proteinuria was found to be significantly more common in eclampsia group (88%) as compared with preeclampsia (65%, P = 0.001). Regarding maternal outcome, mortality was observed in 6 (5 %) women in eclampsia group, while none in preeclampsia group. The maternal morbidity due to infectious causes was also found to be high (34%) in our study population. This morbidity has also led to prolonged hospital stay in these women (14.98 ± 9.6 days) as compared with the other women (9.97 ± 4.58 days, P < 0.001). A total of 27% of patient in eclampsia group required admission to intensive care in eclampsia group, while it was 10% in preeclampsia group (P = 0.03). The most common mode of the delivery in both groups was through lower segment cesarean section (LSCS).
The fetal mortality was high (17%) in eclampsia group as compared with 6% in preeclampsia group (P = 0.09). Fetal distress and intrauterine growth retardation (IUGR) were not significantly different in the two groups. A total of 50% of the newborn were having birth weight between 1.5 and 2.5 kg which was consequent with their premature birth.
Drug Prescription Characteristics
Average number of drugs prescribed in women of preeclampsia, antepartum eclampsia, and postpartum eclampsia were 13.2, 14.9, and 14.2, respectively. The percentage distribution of different classes of drugs in three groups is shown in [Figure 3]. Antibiotics are the most common class of the drugs prescribed in all the groups, followed by vitamin and calcium supplements. Anticonvulsants were the next most frequently prescribed drug in eclampsia women (both ante and post partum), while antihypertensives were more common in cases of preeclampsia women and also represent the next most common class of drugs in case of eclampsia. Antiemetic, gastroprotective, and analgesics constituted the other classes of drugs prescribed in these patient populations as shown in [Figure 3].
Prescription Pattern of Antihypertensive Agents
The prescription pattern of individual antihypertensive drugs is described in [Table 2]. The average number of antihypertensives prescribed was 1.8 drugs per patient (1.8 ± 1.6) in preeclampsia. In antepartum eclampsia, an average of 1.7 (1.7 ± 1.4) and in postpartum eclampsia an average of 1.6 drugs (1.6 ± 1.3) were antihypertensives. Calcium channel blockers (CCBs) were the most frequently prescribed antihypertensives (71%), followed by β-blockers (21%). Sympatholytics (alpha methyldopa) and diuretics (furosemide) were prescribed in 18% of women, while nitrates were given to 11 % of women population. Nifedipine and amlodipine were the CCBs of choice prescribed, while atenolol was the preferred β-blocker. Few patients also received labetolol; metoprolol and bisoprolol were also prescribed.
|Table 2: Prescription pattern of antihypertensive and anticonvulsant drugs|
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Prescription Pattern of Anticonvulsant Drugs
The average number of anticonvulsant prescribed were 0.3 drugs per woman (0.3 ± 0.7) in preeclampsia, 1.9 drugs per woman (1.9 ± 1.0) in antepartum eclampsia and 1.8 drugs on an average (1.8 ± 0.7) in case of postpartum eclampsia. Magnesium sulphate (MgSO 4 ) was clearly the anticonvulsant of choice, prescribed in 116 women. All (100%) of the patients with eclampsia received MgSO 4 either alone or in combination, while only three (5.8%) prescriptions in severe preeclampsia group received it [Table 2]. The cases showing disorientation, or diminished patellar reflex, decreased urine output, respiratory irregularity, or recurrence of seizures, while on MgSO 4 therapy were simultaneously put on intervenous phenytoin therapy. The choice of addition of third drug was to control seizure purely as trial and error in solitary atypical cases not controlled by standard approach. The duration of MgSO 4 therapy was quite variable as depicted in [Table 2]. The reasons of discontinuation of MgSO 4 therapy were adequate seizure control or appearance of any of the above mentioned adverse effects.
Prescription Pattern of Antibiotics
A combination of metronidazole, gentamicin, and cephalosporin (mostly third generation) was the most common antibiotic regimen prescribed, representing 63% of the antibiotic use. Among these women, majority underwent emergency LSCS which justifies the use of these antibiotics. This was followed by the combination of metronidazole and third generation cephalosporins in 23% women in the study cohort. Very few women received penicillin along with either metronidazole or gentamicin. A small percentage (6.6%) of women did not receive any antibiotic.
| » Discussion|| |
The primary objective of management in women with pregnancy-induced hypertension is to protect the safety of the mother and the fetus and the subsequent delivery of a healthy baby. The reported outcomes of women with severe preeclampsia and eclampsia are limited. To add to this body of literature, we reviewed the obstetric outcome and medication utilization of 164 inpatiently pregnancies with superimposed preeclampsia/eclampsia at our institution. 
Eclampsia has been found to be primarily a condition of young primigravid women, consistent with the current findings that 50% of patients were ≤25 years old and 62% were primigravidas [Table 1]. Most studies found that eclampsia occurred in the extremes of ages. With the establishment of antenatal care and essential obstetrics services, the incidence of eclampsia has been declining. Most authorities recommend hospitalization only in cases of severe pre eclampsia or eclampsia. However, majority of the pregnant women presenting to our health facility are illiterate with only rudimentary medical knowledge of their own pregnancies. Because of these reasons inpatient management if preferred in these cases for close monitoring and timely drug administration.
The target population in this study were women with severe preeclampsia/eclampsia who remained inpatient during rest of their pregnancy. Surprisingly, majority had no prior antenatal check-up and our study cohort women who presented for initial prenatal care with severely elevated blood pressure had a similar mean gestational age at diagnosis of superimposed preeclampsia, but a shorter latency period from diagnosis to delivery. In cases of preeclampsia, 64% were unbooked pregnancies with no prior health check-up during pregnancy and 77% of these cases underwent emergency caesarean section. In eclampsia group, 52% cases were unbooked pregnancies. Regarding the fetal outcome, the complications were fetal distress, IUGR and perinatal mortality.
The average number of the prescribed medications is too high (13.2). However, this can be due to the fact that this number includes prescribed haematinics and calcium tablets, gastroprotectives (including gelusil), antiemetics, antihypertensives, antibiotics as well as anticonvulsants. Moreover, these represent the numbers of different drugs prescribed to each patient during the entire duration of the hospital stay.
Antihypertensive drug therapy is recommended only for those with systolic blood pressure >160 mm Hg and diastolic blood pressure >105 mm Hg.  A total of 86% of our study cohort had hypertension. Thus, an average prescription of 1.8 antihypertensive medications is justified in the study cohort of women with severe preeclampsia/eclampsia. There is ongoing debate regarding impaired intrauterine foetal growth especially with β-blocker therapy. 
CCBs were the most common class of antihypertensive prescribed to 71.7% of the women. Nifedipine was the most common individual antihypertensive prescribed. However, 52 of the 74 women (70%) received sublingual nifedipine which is against the recommendations for rational use of antihypertensive. Rapid acting nifedipine should not be used for treating hypertension or hypertensive emergencies especially in pregnancy because it has been associated with fatal and nonfatal untoward cardiovascular events as well as compromised placental perfusion. , The rapid fall in blood pressure can be detrimental to the fetus. The rampant use of sublingual nifedipine as in our study is considered irrational. Amlodipine was also used to some extent both as single ingredient and as fixed dose combination (FDC) with atenolol in 13% of the women. This was the only FDC used in the study.
The use of atenolol early in pregnancy is associated with fetal growth impairment. Most authorities recommend the total avoidance in early pregnancy and cautious use in late pregnancy.  On analysis, it was found that in all 25 out of the 29 cases, it was prescribed post delivery.
According to the recommendations women well-controlled on antihypertensive therapy before pregnancy may be kept on the same agents (with the exception of angiotensin (AT)-converting enzyme inhibitors, AT-II receptor antagonists) during pregnancy. 
In the present study, it was surprising to observe the low use of labetalol as antihypertensive for preeclampsia and eclampsia. With its efficacy, convenient routes of administration and better safety profile in pregnancy, labetalol has become the drug of choice for the acute control of blood pressure in cases of pregnancy-induced hypertension worldwide.  According to the prescribers, the high cost of the drug does not allow prescribing it routinely.
Anticonvulsant therapy is indicated both to prevent the occurrence and control of convulsions in preeclampsia  and eclampsia.  Magpie trial has shown that magnesium sulphate halves the risk of eclampsia in preeclamptic women. Magnesium sulphate has now become the drug of choice for treating and preventing convulsions in women with preeclampsia/eclampsia.  The Collaborative Eclampsia Trial provides strong evidence for the routine use of magnesium sulphate rather than either diazepam or phenytoin for the management of eclampsia.  Magnesium sulphate was found to be the most common anticonvulsant being prescribed closely followed by phenytoin. The use of magnesium sulphate is expected and recommended for controlling convulsions in eclampsia, but such high use of phenytoin along with magnesium sulphate mandates further inquiry.
About 60% of different drugs used in the obstetric practice were from the National Essential drug list or complementary drug list. This is quite expected, considering the severity of illnesses of the women. However, a relatively higher proportion of drugs (80%-90%) were prescribed as trade names.
Prophylactic antibiotics prescription in pregnancy is not recommended. Cesarean delivery is an important factor for development of postpartum maternal infection and use of prophylactic antibiotics.  Our study revealed a relatively higher frequency of antibiotic usage in all the three subsets of women. This may be because majority were delivered by caesarean section. Evidence shows that antibiotic prophylaxis in cases of caesarean delivery reduces the incidence of maternal infectious morbidity.  The trials evaluating the use of prophylactic antibiotics have also shown that a single preoperative dose of antibiotic is sufficient and multiple dose regimes do not offer any added benefit to reduce the infectious morbidity.  The choice of antibiotics and duration of their use is based on the ''risk'' status of the patient. The patients are categorized as high risk if they were unbooked pregnancies, presenting to this particular health facility for the first time, usually of low socioeconomic status with no prior antenatal check-up which is usually the case in our study setting. Further, the prescribers point to the fact that maximum number of women undergo emergency caesarean section and general standards of the antenatal and postnatal wards are such that development of infectious morbidity was more likely.  However, such an excessive use of antibiotic is alarming and irrational. This needs further investigation to curtail the use of antimicrobials in these patients.
| » Conclusion|| |
Most common antihypertensive used were CCBs and anticonvulsant magnesium sulphate. Labetalol was infrequently used. Protocols for the management of eclampsia, including antihypertensive and anticonvulsant therapies, should be available and reviewed regularly to substantially improve the standard of care and reduce the prevalence of this complication of pregnancy. Excessive use of antibiotics must also be curtailed.
| » References|| |
|1.||Magee LA, Helewa M, Rey E, von Dadelszen P. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can 2008;30:S1-48. |
|2.||Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa M, et al., CHIPS Pilot Trial Collaborative Group. The control of hypertension in pregnancy study pilot trial. Br J Obstet Gynaecol 2007;114:e13-20. |
|3.||Kacew S. Fetal consequences and risks attributed to the use of prescribed and over-the-counter (OTC) preparations during pregnancy. Int J Clin Pharmacol Ther 1994;32:335-43. |
|4.||Cragan JD, Friedman JM, Holmes LB, Uhl K, Green NS, Riley L. Ensuring the safe and effective use of medications during pregnancy: Planning and prevention through preconception care. Matern Child Health J 2006;10:129-35. |
|5.||Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication use during pregnancy and lactation: An urgent call for public health action. J Womens Health 2005;14:104-9. |
|6.||Introduction to Drug Utilization Research [Internet] 2003 [cited 2013 Dec 12]. WHO International Working Group for Drug Statistics Methodology, WHO Collaborating Centre for Drug Statistics Methodology, WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacology. Geneva: World Health Organization, 2003.. Available from: http://www.whocc.no/filearchive/publications/drug_utilization_research.pdf |
|7.||Diagnosis and management of preeclampsia and eclampsia. American college of obstetrics and gynaecology (ACOG) practice bulletin Number 33, 2002. Obstet Gynecol 2002;99:159-67. |
|8.||Roberts JM, Pearson GD, Cutler JA, Lindheimer MD, National Heart Lung and Blood Institute. Summary of the NHLBI Working Group on Research on Hypertension during pregnancy. Hypertens Pregnancy 2003;22:109-27. |
|9.||Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al., Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: A randomised placebo-controlled trial. Lancet 2002;359:1877-90. |
|10.||Duley L. Magnesium sulphate regimens for women with eclampsia: Messages from the Collaborative Eclampsia Trial. Br J Obstet Gynaecol 1996;103:103-5. |
|11.||Sibai BM. Diagnosis, prevention and management of eclampsia. Obstet Gynecol 2005;105:402-10. |
|12.||Chambers CD, Polifka JE, Friedman JM. Drug safety in pregnant women and their babies: Ignorance not bliss. Clin Pharmacol Ther 2008;83:181-3. |
|13.||von Dadelszen P, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: An updated metaregression analysis. J Obstet Gynaecol Can 200224:941-5. |
|14.||Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328-31. |
|15.||Brown MA, Buddle ML, Farrell T, Davis GK. Efficacy and safety of nifedipine tablets for the acute treatment of severe hypertension in pregnancy. Am J Obstet Gynecol 2002;187:1046-50. |
|16.||Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: Management of hypertension in pregnancy. BMJ 1999;318:1332-6. |
|17.||Sibai BM, Ross MG. Hypertension in gestational diabetes mellitus: Pathophysiology and long-term consequences. J Matern Fetal Neonatal Med 2010;23:229-33. |
|18.||Sibai BM. Imitators of severe pre-eclampsia/eclampsia. Clin Perinatol 2004;31:835-52. |
|19.||Chien PF, Khan KS, Arnott N. Magnesium sulphate in the treatment of eclampsia and pre-eclampsia: An overview of the evidence from randomised trials. Br J Obstet Gynaecol 1996;103:1085-91. |
|20.||Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995;345:1455-63. |
|21.||Burrows LJ, Meyn LA, Weber AM. Maternal morbidity associated with vaginal versus cesarean delivery. Obstet Gynecol 2004;103:907-12. |
|22.||Bagratee JS, Moodley J, Kleinschmidt I, Zawilski W. A randomised controlled trial of antibiotic prophylaxis in elective caesarean delivery. BJOG 2001;108:143-8. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]