metronidazole has been researched along with Premature Birth in 32 studies
Metronidazole: A nitroimidazole used to treat AMEBIASIS; VAGINITIS; TRICHOMONAS INFECTIONS; GIARDIASIS; ANAEROBIC BACTERIA; and TREPONEMAL INFECTIONS.
metronidazole : A member of the class of imidazoles substituted at C-1, -2 and -5 with 2-hydroxyethyl, nitro and methyl groups respectively. It has activity against anaerobic bacteria and protozoa, and has a radiosensitising effect on hypoxic tumour cells. It may be given by mouth in tablets, or as the benzoate in an oral suspension. The hydrochloride salt can be used in intravenous infusions. Metronidazole is a prodrug and is selective for anaerobic bacteria due to their ability to intracellularly reduce the nitro group of metronidazole to give nitroso-containing intermediates. These can covalently bind to DNA, disrupting its helical structure, inducing DNA strand breaks and inhibiting bacterial nucleic acid synthesis, ultimately resulting in bacterial cell death.
Premature Birth: CHILDBIRTH before 37 weeks of PREGNANCY (259 days from the first day of the mother's last menstrual period, or 245 days after FERTILIZATION).
| Excerpt | Relevance | Reference |
|---|---|---|
| "Studies investigating the association between gestational use of oral metronidazole on human subjects and the risk of preterm birth or/and birth defects were systematically retrieved from MEDLINE and EMBASE databases." | 8.91 | The use of metronidazole during pregnancy: a review of evidence. ( Berard, A; Ferreira, E; Santos, F; Sheehy, O, 2015) |
| " A recent clinical recommendation by a guidelines group of the Danish Society of Obstetrics and Gynecology advised against the use of clindamycin for the treatment of bacterial vaginosis in pregnancy to reduce the risk of spontaneous preterm birth based on lack of evidence of efficacy." | 7.85 | The treatment of bacterial vaginosis in pregnancy with clindamycin to reduce the risk of infection-related preterm birth: a response to the Danish Society of Obstetrics and Gynecology guideline group's clinical recommendations. ( Jørgensen, JS; Keelan, JA; Lamont, RF; Larsson, PG, 2017) |
| "To assess whether treatment with metronidazole during pregnancy is associated with preterm birth, low birth weight, or major congenital anomalies, we conducted chart reviews and an analysis of electronic data from a cohort of women delivering at an urban New York State hospital." | 7.78 | Investigation of metronidazole use during pregnancy and adverse birth outcomes. ( Aubry, R; Baras, DC; Koss, CA; Koumans, EH; Lane, SD; Marcus, M; Markowitz, LE, 2012) |
| "We have previously found an association between the combination of topical and vaginal clotrimazole treatment during pregnancy and a decreased prevalence of preterm births in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities." | 7.72 | Preterm birth reduction after clotrimazole treatment during pregnancy. ( Czeizel, AE; Fladung, B; Vargha, P, 2004) |
| "Metronidazole was found to be effective in preventing preterm births when used in conjunction with other antibiotics." | 5.62 | The safety of metronidazole in pregnancy. ( Bloom, K; Nwosu, OC, 2021) |
| "Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation." | 5.41 | Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis. ( Andrews, WW; Bhandaru, V; Emel, LM; Goldenberg, RL; Hoffman, MK; Kiss, H; Klebanoff, MA; Lamont, RF; Larsen, MD; Larsson, PG; Odendaal, HJ; Petricevic, L; Schuit, E; Seed, PT; Shennan, A; Ugwumadu, A; Weiner, S, 2023) |
| "Women with a spontaneous preterm birth < 34 weeks' gestational age were randomized at 4 months' postpartum to receive oral azithromycin 1 g twice (4 days apart) plus sustained-release metronidazole 750 mg daily for 7 days, or identical-appearing placebos." | 5.12 | Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. ( Andrews, WW; Cliver, SP; Conner, M; Copper, R; Goldenberg, RL; Hauth, JC, 2006) |
| "Studies investigating the association between gestational use of oral metronidazole on human subjects and the risk of preterm birth or/and birth defects were systematically retrieved from MEDLINE and EMBASE databases." | 4.91 | The use of metronidazole during pregnancy: a review of evidence. ( Berard, A; Ferreira, E; Santos, F; Sheehy, O, 2015) |
| "Macrolides and clindamycin, given during the second trimester of pregnancy, are associated with a lower rate of preterm delivery, whereas second-trimester metronidazole used alone is linked with a greater risk of preterm delivery in a high-risk population." | 4.84 | The effect of second-trimester antibiotic therapy on the rate of preterm birth. ( Bujold, E; Morency, AM, 2007) |
| " A recent clinical recommendation by a guidelines group of the Danish Society of Obstetrics and Gynecology advised against the use of clindamycin for the treatment of bacterial vaginosis in pregnancy to reduce the risk of spontaneous preterm birth based on lack of evidence of efficacy." | 3.85 | The treatment of bacterial vaginosis in pregnancy with clindamycin to reduce the risk of infection-related preterm birth: a response to the Danish Society of Obstetrics and Gynecology guideline group's clinical recommendations. ( Jørgensen, JS; Keelan, JA; Lamont, RF; Larsson, PG, 2017) |
| " For this reason, the present study was conducted to investigate the effectiveness of octenidine dihydrochloride/phenoxyethanol (OHP) in comparison to antimicrobial therapies in pregnant women in hospital suffering from different types of vaginitis." | 3.81 | Study results on the use of different therapies for the treatment of vaginitis in hospitalised pregnant women. ( Novakov Mikić, A; Stojic, S, 2015) |
| "To assess whether treatment with metronidazole during pregnancy is associated with preterm birth, low birth weight, or major congenital anomalies, we conducted chart reviews and an analysis of electronic data from a cohort of women delivering at an urban New York State hospital." | 3.78 | Investigation of metronidazole use during pregnancy and adverse birth outcomes. ( Aubry, R; Baras, DC; Koss, CA; Koumans, EH; Lane, SD; Marcus, M; Markowitz, LE, 2012) |
| "To investigate the association between treatment of maternal trichomoniasis with oral metronidazole and preterm birth." | 3.75 | Treatment of trichomoniasis in pregnancy and preterm birth: an observational study. ( Barnes, TL; Hardin, J; Mann, JR; McDermott, S; Zhou, L, 2009) |
| "The purpose of this study was to determine if a change in the vaginal flora was associated with an increased risk of preterm birth, and to determine if metronidazole therapy before 32 weeks increased the risk of preterm birth." | 3.73 | Is a change in the vaginal flora associated with an increased risk of preterm birth? ( Carey, JC; Klebanoff, MA, 2005) |
| "We have previously found an association between the combination of topical and vaginal clotrimazole treatment during pregnancy and a decreased prevalence of preterm births in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities." | 3.72 | Preterm birth reduction after clotrimazole treatment during pregnancy. ( Czeizel, AE; Fladung, B; Vargha, P, 2004) |
| "The relationship between bacterial vaginosis (BV) and preterm delivery has become well known in recent years, although there are few studies on: (i) the differences in test results during the early gestational (EGP) and middle gestational (MGP) periods; (ii) the significance of the intermediate (I) group that does not develop overt BV; or (iii) the therapeutic effects of metronidazole." | 2.90 | Association between preterm delivery and bacterial vaginosis with or without treatment. ( Doh, K; Kotani, Y; Mandai, M; Matsumura, N; Shimaoka, M; Suzuki, A; Tsuji, I; Yo, Y, 2019) |
| "Accuracy of screening tests for bacterial vaginosis varies." | 2.66 | Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. ( Berkman, N; Clark, R; Kahwati, LC; Patel, SV; Urrutia, R; Viswanathan, M; Zeng, J, 2020) |
| "Preterm birth is the major cause of perinatal mortality and morbidity in high-income countries." | 2.50 | The early use of appropriate prophylactic antibiotics in susceptible women for the prevention of preterm birth of infectious etiology. ( Joergensen, JS; Kjær Weile, LK; Lamont, RF, 2014) |
| "Metronidazole was found to be effective in preventing preterm births when used in conjunction with other antibiotics." | 1.62 | The safety of metronidazole in pregnancy. ( Bloom, K; Nwosu, OC, 2021) |
| "Vulvovaginal candidiasis affects 75% of women at least once." | 1.42 | Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. ( van Schalkwyk, J; Yudin, MH, 2015) |
| "As metronidazole effectively treats full BV, but is ineffective against other forms of AVF, the present data may help to explain why its use to prevent PTB has not been successful in most studies." | 1.35 | Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy. ( Bellen, G; Donders, GG; Reybrouck, R; Riphagen, I; Van Calsteren, K; Van den Bosch, T; Van Lierde, S, 2009) |
| Timeframe | Studies, this research(%) | All Research% |
|---|---|---|
| pre-1990 | 0 (0.00) | 18.7374 |
| 1990's | 0 (0.00) | 18.2507 |
| 2000's | 12 (37.50) | 29.6817 |
| 2010's | 14 (43.75) | 24.3611 |
| 2020's | 6 (18.75) | 2.80 |
| Authors | Studies |
|---|---|
| Cenkowski, M | 1 |
| Wudel, B | 1 |
| Poliquin, V | 1 |
| Kissinger, PJ | 1 |
| Gaydos, CA | 1 |
| Seña, AC | 1 |
| Scott McClelland, R | 1 |
| Soper, D | 1 |
| Secor, WE | 1 |
| Legendre, D | 1 |
| Workowski, KA | 1 |
| Muzny, CA | 1 |
| Klebanoff, MA | 4 |
| Schuit, E | 1 |
| Lamont, RF | 3 |
| Larsson, PG | 2 |
| Odendaal, HJ | 1 |
| Ugwumadu, A | 1 |
| Kiss, H | 1 |
| Petricevic, L | 1 |
| Andrews, WW | 4 |
| Hoffman, MK | 1 |
| Shennan, A | 2 |
| Seed, PT | 1 |
| Goldenberg, RL | 4 |
| Emel, LM | 1 |
| Bhandaru, V | 1 |
| Weiner, S | 1 |
| Larsen, MD | 1 |
| Kahwati, LC | 1 |
| Clark, R | 1 |
| Berkman, N | 1 |
| Urrutia, R | 1 |
| Patel, SV | 1 |
| Zeng, J | 1 |
| Viswanathan, M | 1 |
| Jin, WH | 1 |
| Ha Kim, Y | 1 |
| Kim, JW | 1 |
| Kim, TY | 1 |
| Kim, A | 1 |
| Yang, Y | 1 |
| Nwosu, OC | 1 |
| Bloom, K | 1 |
| Shimaoka, M | 1 |
| Yo, Y | 1 |
| Doh, K | 1 |
| Kotani, Y | 1 |
| Suzuki, A | 1 |
| Tsuji, I | 1 |
| Mandai, M | 1 |
| Matsumura, N | 1 |
| Joergensen, JS | 1 |
| Kjær Weile, LK | 1 |
| Han, C | 1 |
| Wu, W | 1 |
| Fan, A | 1 |
| Wang, Y | 1 |
| Zhang, H | 1 |
| Chu, Z | 1 |
| Wang, C | 1 |
| Xue, F | 1 |
| Novakov Mikić, A | 1 |
| Stojic, S | 1 |
| Sheehy, O | 1 |
| Santos, F | 1 |
| Ferreira, E | 1 |
| Berard, A | 1 |
| van Schalkwyk, J | 1 |
| Yudin, MH | 1 |
| Birck, MM | 1 |
| Nguyen, DN | 1 |
| Cilieborg, MS | 1 |
| Kamal, SS | 1 |
| Nielsen, DS | 1 |
| Damborg, P | 1 |
| Olsen, JE | 1 |
| Lauridsen, C | 1 |
| Sangild, PT | 1 |
| Thymann, T | 1 |
| Haahr, T | 1 |
| Ersbøll, AS | 1 |
| Karlsen, MA | 1 |
| Svare, J | 1 |
| Sneider, K | 1 |
| Hee, L | 1 |
| Weile, LK | 1 |
| Ziobrowska-Bech, A | 1 |
| Østergaard, C | 1 |
| Jensen, JS | 1 |
| Helmig, RB | 1 |
| Uldbjerg, N | 1 |
| Keelan, JA | 1 |
| Jørgensen, JS | 1 |
| Kurtzman, J | 1 |
| Chandiramani, M | 1 |
| Briley, A | 1 |
| Poston, L | 1 |
| Das, A | 1 |
| Mann, JR | 1 |
| McDermott, S | 1 |
| Zhou, L | 1 |
| Barnes, TL | 1 |
| Hardin, J | 1 |
| Donders, GG | 1 |
| Van Calsteren, K | 1 |
| Bellen, G | 1 |
| Reybrouck, R | 1 |
| Van den Bosch, T | 1 |
| Riphagen, I | 1 |
| Van Lierde, S | 1 |
| Stringer, E | 1 |
| Read, JS | 1 |
| Hoffman, I | 1 |
| Valentine, M | 1 |
| Aboud, S | 1 |
| Milewicz, T | 1 |
| Hejnar, J | 1 |
| Jach, R | 1 |
| Jaworowski, AP | 1 |
| Piskorz, T | 1 |
| Gach, A | 1 |
| Krzysiek, J | 1 |
| Briery, CM | 1 |
| Chauhan, SP | 1 |
| Magann, EF | 1 |
| Cushman, JL | 1 |
| Morrison, JC | 1 |
| Sungkar, A | 1 |
| Purwosunu, Y | 1 |
| Aziz, MF | 1 |
| Pratomo, H | 1 |
| Sutrisna, B | 1 |
| Sekizawa, A | 1 |
| Koss, CA | 1 |
| Baras, DC | 1 |
| Lane, SD | 1 |
| Aubry, R | 1 |
| Marcus, M | 1 |
| Markowitz, LE | 1 |
| Koumans, EH | 1 |
| Czeizel, AE | 1 |
| Fladung, B | 1 |
| Vargha, P | 1 |
| Riggs, MA | 1 |
| Carey, JC | 1 |
| Hauth, JC | 2 |
| Cliver, SP | 2 |
| Copper, R | 1 |
| Conner, M | 2 |
| Morency, AM | 3 |
| Bujold, E | 3 |
| Tita, AT | 1 |
| Goepfert, AR | 1 |
| Hendler, I | 1 |
| Carey, CJ | 1 |
| Noble, WD | 1 |
| Sibai, BM | 1 |
| Hillier, SL | 1 |
| Dudley, D | 1 |
| Ernest, JM | 1 |
| Leveno, KJ | 1 |
| Wapner, R | 1 |
| Iams, JD | 1 |
| Varner, M | 1 |
| Moawad, A | 1 |
| Miodovnik, M | 1 |
| O'Sullivan, MJ | 1 |
| Van Dorsten, PJ | 1 |
| Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
|---|---|---|---|---|---|---|---|
| New Tool to Predict Risk of Spontaneous Preterm Birth in Asymptomatic High-risk Women[NCT03062020] | 258 participants (Anticipated) | Interventional | 2016-11-16 | Recruiting | |||
| Preventing Preterm Birth With Probiotics - Pilot Randomised Trial[NCT02692820] | 304 participants (Actual) | Interventional | 2016-05-31 | Completed | |||
| Study of Antenatal Model to Prevent Preterm Delivery: Early Detection and Treatment of Bacterial Vaginosis[NCT01232192] | 220 participants (Anticipated) | Interventional | 2009-01-31 | Recruiting | |||
| Clindamycin to Reduce Preterm Birth in a Low Resource Setting: A Randomized Placebo-controlled Trial[NCT01800825] | Phase 4 | 1,726 participants (Actual) | Interventional | 2013-07-31 | Completed | ||
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] | |||||||
8 reviews available for metronidazole and Premature Birth
| Article | Year |
|---|---|
Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis.
Topics: Anti-Bacterial Agents; Clindamycin; Female; Humans; Infant, Newborn; Metronidazole; Pregnancy; Prema | 2023 |
Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
Topics: Anti-Bacterial Agents; Asymptomatic Infections; Clindamycin; Female; Humans; Mass Screening; Metroni | 2020 |
The early use of appropriate prophylactic antibiotics in susceptible women for the prevention of preterm birth of infectious etiology.
Topics: Anti-Bacterial Agents; Clindamycin; Female; Humans; Infant, Newborn; Metronidazole; Pregnancy; Pregn | 2014 |
Diagnostic and therapeutic advancements for aerobic vaginitis.
Topics: Bacteria, Aerobic; Female; Humans; Infant, Newborn; Lactobacillus; Metronidazole; Pregnancy; Pregnan | 2015 |
The use of metronidazole during pregnancy: a review of evidence.
Topics: Abnormalities, Drug-Induced; Adult; Anti-Bacterial Agents; Female; Humans; Infant, Newborn; Metronid | 2015 |
Treatment of bacterial vaginosis in pregnancy in order to reduce the risk of spontaneous preterm delivery - a clinical recommendation.
Topics: Anti-Bacterial Agents; Clindamycin; Female; Humans; Metronidazole; Pregnancy; Pregnancy Complication | 2016 |
Treatment of vaginal infections to prevent preterm birth: a meta-analysis.
Topics: Anti-Infective Agents; Female; Humans; Metronidazole; Pregnancy; Pregnancy Complications, Infectious | 2004 |
The effect of second-trimester antibiotic therapy on the rate of preterm birth.
Topics: Anti-Bacterial Agents; Clindamycin; Female; Humans; Macrolides; Metronidazole; Pregnancy; Pregnancy | 2007 |
8 trials available for metronidazole and Premature Birth
| Article | Year |
|---|---|
Diagnosis and Management of Trichomonas vaginalis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines.
Topics: Centers for Disease Control and Prevention, U.S.; Female; HIV Infections; Humans; Infant, Newborn; M | 2022 |
Association between preterm delivery and bacterial vaginosis with or without treatment.
Topics: Adult; Female; Humans; Male; Metronidazole; Pregnancy; Pregnancy Complications, Infectious; Prematur | 2019 |
Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery.
Topics: Adult; Anti-Infective Agents; Female; Fetal Blood; Fibronectins; Gestational Age; Humans; Kaplan-Mei | 2009 |
Treatment of trichomoniasis in pregnancy in sub-Saharan Africa does not appear to be associated with low birth weight or preterm birth.
Topics: Adult; Africa South of the Sahara; Anti-Infective Agents; Cohort Studies; Erythromycin; Female; Huma | 2010 |
Influence of early self-diagnosis and treatment of bacterial vaginosis on preterm birth rate.
Topics: Anti-Infective Agents; Diagnostic Self Evaluation; Female; Gentian Violet; Humans; Hydrogen-Ion Conc | 2012 |
Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial.
Topics: Adult; Anti-Bacterial Agents; Azithromycin; Double-Blind Method; Female; Humans; Metronidazole; Prec | 2006 |
Clinical trial of interconceptional antibiotics to prevent preterm birth: subgroup analyses and possible adverse antibiotic-microbial interaction.
Topics: Adult; Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Bacterial Infections; Double-Bli | 2007 |
The relationship between resolution of asymptomatic bacterial vaginosis and spontaneous preterm birth in fetal fibronectin-positive women.
Topics: Adult; Anti-Infective Agents; Comorbidity; Female; Fibronectins; Humans; Metronidazole; Pregnancy; P | 2007 |
16 other studies available for metronidazole and Premature Birth
| Article | Year |
|---|---|
Vaginal trichomoniasis.
Topics: Administration, Oral; Anti-Infective Agents; Canada; Drug Resistance; Female; Fetal Membranes, Prema | 2022 |
Antibiotic treatment of amniotic fluid "sludge" in patients during the second or third trimester with uterine contraction.
Topics: Adult; Amniotic Fluid; Anti-Bacterial Agents; Ceftriaxone; Clarithromycin; Cohort Studies; Female; H | 2021 |
The safety of metronidazole in pregnancy.
Topics: Anti-Bacterial Agents; Female; Humans; Infant, Newborn; Metronidazole; Pregnancy; Pregnancy Complica | 2021 |
Study results on the use of different therapies for the treatment of vaginitis in hospitalised pregnant women.
Topics: Adolescent; Adult; Anti-Infective Agents; Candidiasis, Vulvovaginal; Ethylene Glycols; Female; Human | 2015 |
Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Canada; Candidiasis, Vulvovaginal; Clindamycin; Female | 2015 |
Enteral but not parenteral antibiotics enhance gut function and prevent necrotizing enterocolitis in formula-fed newborn preterm pigs.
Topics: Ampicillin; Animals; Animals, Newborn; Anti-Bacterial Agents; Biological Availability; Disease Model | 2016 |
The treatment of bacterial vaginosis in pregnancy with clindamycin to reduce the risk of infection-related preterm birth: a response to the Danish Society of Obstetrics and Gynecology guideline group's clinical recommendations.
Topics: Abortion, Spontaneous; Anti-Bacterial Agents; Clindamycin; Female; Humans; Infant, Low Birth Weight; | 2017 |
Treatment of trichomoniasis in pregnancy and preterm birth: an observational study.
Topics: Adult; Antiprotozoal Agents; Female; Humans; Medicaid; Metronidazole; Pregnancy; Premature Birth; Re | 2009 |
Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy.
Topics: Adult; Anti-Infective Agents; Female; Humans; Metronidazole; Mycoplasma hominis; Mycoplasma Infectio | 2009 |
[Bacterial vaginosis and preterm delivery risk].
Topics: Administration, Intravaginal; Adult; Anti-Bacterial Agents; Causality; Chi-Square Distribution; Como | 2010 |
Treatment of bacterial vaginosis does not reduce preterm birth among high-risk asymptomatic women in fetal fibronectin positive patients.
Topics: Adult; Anti-Infective Agents; Apgar Score; Birth Weight; Chi-Square Distribution; Enzyme-Linked Immu | 2011 |
Investigation of metronidazole use during pregnancy and adverse birth outcomes.
Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antifungal Agents; Cohort Studies; Female; Fungi; Hu | 2012 |
Preterm birth reduction after clotrimazole treatment during pregnancy.
Topics: Administration, Intravaginal; Adolescent; Adult; Anti-Infective Agents; Anti-Infective Agents, Local | 2004 |
Is a change in the vaginal flora associated with an increased risk of preterm birth?
Topics: Administration, Intravaginal; Adult; Case-Control Studies; Cohort Studies; Confidence Intervals; Esc | 2005 |
Comment on "Pregnancy outcome after early detection of bacterial vaginosis" [Eur. J. Obstet. Gynecol. Reprod. Biol. 128 (2006) 40-45].
Topics: Adult; Animals; Antiprotozoal Agents; Clindamycin; Female; Humans; Infant, Newborn; Metronidazole; P | 2007 |
Antibiotics for the prevention of preterm birth.
Topics: Anti-Infective Agents; Antibiotic Prophylaxis; Clindamycin; Female; Humans; Meta-Analysis as Topic; | 2008 |