Misoprostol

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

|preview=

}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=22385CCCC[C@](C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC1S/C22H38O5/c1-4-5-14-22(2,26)15-10-12-18-17(19(23)16-20(18)24)11-8-6-7-9-13-21(25)27-3/h10,12,17-18,20,24,26H,4-9,11,13-16H2,1-3H3/b12-10+/t17-,18-,20-,22?/m1/s1OJLOPKGSLYJEMD-URPKTTJQSA-NTemplate:StdinchiciteTemplate:Stdinchicite | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.coma689009Misoprostol <ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>XUsed for terminating pregnancyBy mouth, rectal, vaginal, under the tongueCytotec, Misodel, othersA02Template:ATC | _legal_data=<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>S4Hospital use only<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>C1Rx-only<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>POM<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only

| _other_data=Methyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoate

| _image_0_or_2 = Misoprostol.svg | _image_LR =

| _datapage = Misoprostol (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4C1Rx-onlyPOMRx-onlyRx-only | _ATC_prefix_supplemental=A02Template:ATC | _has_EMA_link = | CAS_number=59122-46-2 | PubChem=5282381 | ChemSpiderID=4445541 | ChEBI= | ChEMBL=606 | DrugBank=DB00929 | KEGG=D00419 | _hasInChI_or_Key={{#if:1S/C22H38O5/c1-4-5-14-22(2,26)15-10-12-18-17(19(23)16-20(18)24)11-8-6-7-9-13-21(25)27-3/h10,12,17-18,20,24,26H,4-9,11,13-16H2,1-3H3/b12-10+/t17-,18-,20-,22?/m1/s1OJLOPKGSLYJEMD-URPKTTJQSA-N |yes}} | UNII=0E43V0BB57 | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=456483721}}

Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus.<ref name=Ros2002>Template:Cite journal</ref><ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID).<ref name=AHFS2015/> For abortions it is typically used in conjunction with mifepristone or methotrexate, but can be used alone.<ref name="Zhang_2022">Template:Cite journal</ref> By itself, effectiveness for abortion is between 82% and 100%.<ref name="Moseson_2024">Template:Cite journal</ref> Its efficacy with mifepristone is higher, but varies based on gestational age.<ref>Template:Cite journal</ref> The misoprostol-only abortion regimen is typically recommended only when mifepristone is not available.<ref name="Krugh_2025">Template:Cite book</ref> For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina.<ref name="Zhang_2022" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="ACOG Practice Bulletin No. 200: Ear" /><ref name="Early Pregnancy Loss">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For postpartum bleeding it may also be used rectally.<ref>Template:Cite journal</ref>

Common side effects include diarrhea and abdominal pain.<ref name=AHFS2015/> It is in pregnancy category X, meaning that it is known to result in negative outcomes for the fetus if taken during pregnancy.<ref name=AHFS2015/> In rare cases, uterine rupture may occur.<ref name=AHFS2015/> It is a prostaglandin analogue—specifically, a synthetic prostaglandin E₁ (PGE₁).<ref name=AHFS2015/>

Misoprostol was developed in 1973 and first created for the treatment of gastric ulcers.<ref>Template:Cite book</ref><ref name="Moseson_2024" /> Its first uses for abortion emerged in Latin America in the 1980s, as women noticed miscarriage was a side effect of the medication.<ref name="Moseson_2024" /> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO22nd">Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2015/>

Medical uses

Ulcer prevention

Misoprostol is used for the prevention of NSAID-induced gastric ulcers. It acts upon gastric parietal cells, inhibiting the secretion of gastric acid by G-protein coupled receptor-mediated inhibition of adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased proton pump activity at the apical surface of the parietal cell. Misoprostol is sometimes coprescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g., with diclofenac in Arthrotec).<ref name="Krugh_2025" />

However, even in the treatment of NSAID-induced ulcers, omeprazole proved to be at least as effective as misoprostol,<ref>Template:Cite journal</ref> but was significantly better tolerated, so misoprostol is not considered a first-line treatment. Misoprostol-induced diarrhea and the need for multiple daily doses impairing treatment for gastric ulcers.<ref>Template:Cite journal</ref>

Labor induction

Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix.<ref>Template:Cite journal</ref> It can be less expensive than the other commonly used ripening agent, dinoprostone.<ref name="summers"/>

Oxytocin has long been used as the standard agent for labor induction, but does not work well when the cervix is not yet ripe. Misoprostol also may be used in conjunction with oxytocin.<ref name="summers">Template:Cite journal</ref>

Between 2002 and 2012, a misoprostol vaginal insert was studied, and was approved in the EU.<ref>Template:Cite press release</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It was not approved for use in the United States, and the US FDA still considers cervical ripening and labor induction to be outside of the approved uses for misoprostol.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The vaginal and oral routes of misoprostol for labor induction are comparably effective, and are considered on a case-by-case basis by healthcare professionals.<ref>Template:Cite journal</ref>

Myomectomy

When administered prior to myomectomy in women with uterine fibroids,misoprostol reduces operative blood loss, requirement of blood transfusion, and operating time.<ref>Template:Cite journal</ref>

Abortion

Misoprostol is used either alone or in conjunction with another medication (mifepristone or methotrexate) for medical abortions as an alternative to surgical abortion.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Misoprostol alone is typically only recommended when another medication is not available and is more effective when paired with mifepristone or methotrexate.<ref name="Krugh_2025" /><ref name="WHO_2012" /> Medical abortion has the advantage of being less invasive, and more autonomous, self-directed, and discreet. It is preferred by some women because it feels more natural, as the drugs induce a miscarriage.<ref>Template:Cite journal</ref> It is also more easily accessible in places where abortion is illegal.<ref name="Löwy_2020">Template:Cite journal</ref> The World Health Organization (WHO) provides clear guidelines on the use, benefits and risks of misoprostol for abortions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Misoprostol is most effective when it is used in combination with methotrexate or mifepristone (RU-486).<ref name="WHO_2012">Template:Cite book</ref> Mifepristone blocks signaling by progesterone, causing the uterine lining to degrade, the blood vessels of the cervix and uterus to dilate and causing uterine contraction, similar to a menstrual period, which causes the embryo to detach from the uterine walls.<ref name=AHFS2023>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Misoprostol then dilates the cervix and induces muscle contractions which clear the uterus.<ref>Template:Cite journal</ref><ref name="Allen_2007" /> Misoprostol alone is less effective (typically 88% up to eight-weeks gestation).<ref name="Moseson_2024" /> It is not inherently unsafe if medically supervised, but 1% of women will have heavy bleeding requiring medical attention, some women may have ectopic pregnancy, and the 12% of pregnancies that continue after misoprostol failure are more likely to have birth defects and are usually followed up with surgical intervention.<ref>Template:Cite journal</ref>

Most large studies recommend a protocol for the use of misoprostol in combination with mifepristone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Together they are effective in around 95% for early pregnancies.<ref>Template:Cite book</ref> Misoprostol alone may be more effective in earlier gestation.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Misoprostol can also be used to dilate the cervix in preparation for a first-trimester surgical abortion (either alone or in combination with osmotic dilators), but is not routinely recommended.<ref name="Allen_2007">Template:Cite journal</ref>

Misoprostol by mouth is the least effective treatment for producing complete abortion in a period of 24 hours due to the liver's first-pass effect which reduces the bioavailability of the misoprostol. Vaginal and sublingual routes result in greater efficacy and extended duration of action because these routes of administration allow the drug to be directly absorbed into circulation by bypassing the liver first-pass effect.<ref name="Wu_2017" /><ref name="ACOG Practice Bulletin No. 200: Ear">Template:Cite journal</ref><ref name="Early Pregnancy Loss" />

Hematocrit or Hb tests and Rh testing are recommended before use for abortion confirmation of pregnancy.<ref name="ACOG_2014">Template:Cite journal</ref> Following use, it is recommended that people attend a follow-up visit 2 weeks after treatment. If used for treatment of complete abortion, a pregnancy test, physical examination of the uterus, and ultrasound should be performed to ensure success of treatment. Surgical management is possible in the case of failed treatment.<ref name="Wu_2017" />

Early pregnancy loss

Misoprostol may be used to complete a miscarriage or missed abortion when the body does not expel the embryo or fetus on its own. It can decrease the time to complete expulsion.<ref>Template:Cite journal</ref> Use of a single dose of misoprostol vaginally or buccally is preferred, with additional doses as needed. It also can be used in combination with mifepristone, with a similar regimen to medical abortion.<ref name="ACOG Practice Bulletin No. 200: Ear"/><ref name="Early Pregnancy Loss" />

Postpartum bleeding

Misoprostol is also used to prevent and treat post-partum bleeding. Orally administered misoprostol is marginally less effective than oxytocin.<ref>Template:Cite journal</ref> Rectally administered misoprostol has been shown to be associated with lower rates of side effects compared to other routes.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It is inexpensive and thermostable (not requiring refrigeration like oxytocin), making it a cost-effective and valuable drug to use in the developing world.<ref>Template:Cite journal</ref> A randomized control trial of misoprostol use found a 38% reduction in maternal deaths due to postpartum hemorrhage in resource-poor communities.<ref>Template:Cite journal</ref> Oxytocin must also be given by injection, while misprostol can be given orally or rectally for this use, making it much more useful in areas where nurses and physicians are less available.<ref>Template:Cite journal</ref>

Insertion of intrauterine contraceptive device

In women with prior caesarean section or prior failure of insertion of an intrauterine contraceptive device, pre-procedure administration of misoprostol reduces the rate of failure of insertion of intrauterine contraceptive device. However, due to a higher rate of adverse effects, routine use of misoprostol to dilate the cervix in preparation for intrauterine contraceptive device insertion in other cases is not recommended.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Other

Misoprostol is used for cervical ripening in advance of endometrial biopsy to reduce the need for use of a tenaculum or cervical dilator, but may be associated with increased pain and side effects during and after the procedure.<ref>Template:Cite journal</ref>

There is limited evidence supporting the use of misoprostol for the treatment of trigeminal neuralgia in patients with multiple sclerosis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Adverse effects

The most commonly reported adverse effect of taking misoprostol by mouth for the prevention of stomach ulcers is diarrhea. In clinical trials, an average 13% of people reported diarrhea, which was dose-related and usually developed early in the course of therapy (after 13 days) and was usually self-limiting (often resolving within 8 days), but sometimes (in 2% of people) required discontinuation of misoprostol.<ref name="Cytotec USPI">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The next most commonly reported adverse effects of taking misoprostol by mouth for the prevention of gastric ulcers are: abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation, but none of these adverse effects occurred more often than when taking placebos.<ref name="Cytotec USPI"/>

There are increased side effects with sublingual or oral misoprostol, compared to a low dose (400 μg) vaginal misoprostol. However, low dose vaginal misoprostol was linked with low complete abortion rate.<ref name="Wu_2017">Template:Cite journal File:CC-BY icon.svg Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License Template:Webarchive.</ref> The study concluded that sublingually administered misoprostol dosed at 600 μg or 400 μg had greater instances of fever and diarrhea due to its quicker onset of action, higher peak concentration and bioavailability in comparison to vaginal or oral misoprostol.<ref name="Wu_2017" />

For the indication of medical abortion, bleeding and cramping is commonly experienced after administration of misoprostol. Bleeding and cramping is likely to be greater than that experienced with menses, however, emergency care is advised if bleeding is excessive.<ref name="ACOG_2014" />

Misoprostol should not be taken by pregnant women with wanted pregnancies to reduce the risk of NSAID-induced gastric ulcers because it increases uterine tone and contractions in pregnancy, which may cause partial or complete abortions, and because its use in pregnancy has been associated with birth defects.<ref name="Cytotec USPI"/><ref name="Cytotec UK SPC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

All cervical ripening and induction agents can cause uterine hyperstimulation, which can negatively affect the blood supply to the fetus and increases the risk of complications such as uterine rupture.<ref name="briggs">Template:Cite journal</ref> Concern has been raised that uterine hyperstimulation that occurs during a misoprostol-induced labor is more difficult to treat than hyperstimulation during labors induced by other drugs.<ref>Template:Cite book, which cites:

Template:Cite journal

Template:Cite journal</ref> Because the complications are rare, it is difficult to determine if misoprostol causes a higher risk than do other cervical ripening agents. One estimate is that it would require around 61,000 people enrolled in randomized controlled trials to detect a difference in serious fetal complications and about 155,000 people to detect a difference in serious maternal complications.<ref>Template:Harvnb, which cites:

Template:Cite journal</ref>

Contraindications

It is recommended that medical treatment for missed abortion with misoprostol should only be considered in people without the following contraindications: suspected ectopic pregnancy, use of non-steroidal drugs, signs of pelvic infections or sepsis, unstable hemodynamics, known allergy to misoprostol, previous caesarean section, mitral stenosis, hypertension, glaucoma, bronchial asthma, and remote areas without a hospital nearby.<ref name="Wu_2017" />

Pharmacology

Mechanism of action

Misoprostol, a prostaglandin analogue, binds to myometrial cells to cause strong myometrial contractions leading to expulsion of tissue. This agent also causes cervical ripening with softening and dilation of the cervix. Misoprostol binds to and stimulates prostaglandin EP₂ receptors, prostaglandin EP₃ receptor and prostaglandin EP₄ receptor but not prostaglandin EP₁ receptor and therefore is expected to have a more restricted range of physiological and potentially toxic actions than prostaglandin E₂ or other analogs which activate all four prostaglandin receptors.<ref name="pmid27940058">Template:Cite journal</ref>

Society and culture

In August 2000, a letter from G.D. Searle, LLC, the inventor of the drug,<ref>Template:Cite book</ref> generated controversy by warning against its use by pregnant women because of its ability to induce abortion, citing reports of maternal and fetal deaths when it was used to induce labor.<ref name="goldberg">Template:Cite journal</ref> The American College of Obstetricians and Gynecologists holds that substantial evidence supports the use of misoprostol for induction of labor, a position it reaffirmed in response to the Searle letter.<ref>Template:Harvnb, which cites:

Template:Cite journal

Template:Cite journal</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO22nd" />In 2023, 63% of all abortions in the U.S. were non-surgical, using medications including misoprostol and mifepristone<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

A vaginal form of the medication is sold in the EU under the names Misodel<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and Mysodelle<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> for use in labor induction.<ref>Template:Cite journal</ref>

Black market

Misoprostol is used for self-induced abortions in Latin America, where black market prices exceed US $100 per dose.<ref name="Löwy_2020" /> Illegal medically unsupervised misoprostol abortions are associated with a lower complication rate than other forms of illegal self-induced abortion, but are still associated with a higher complication rate than legal, medically supervised surgical and medical abortion.<ref name="Löwy_2020" /> Failed misoprostol abortions are associated with birth defects in some cases.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Low-income and immigrant populations in New York City have also been observed to use self-administered misoprostol to induce abortions, as this method is much cheaper than a surgical abortion (about $2 per dose).<ref>Template:Cite news</ref> The drug is readily available in Mexico.<ref name=NYT71313>Template:Cite news</ref> Use of misoprostol has also increased in Texas in response to increased regulation of abortion providers.<ref>Template:Cite news</ref> Following the United States Supreme Court decision of Dobbs v. Jackson Women's Health Organization, many states restricted access to legal abortion services, including medication abortion using misoprostol. As a result of these restrictions, it was reported that there was an increase in self-managed abortions by women in the United States. Many women purchased the pills from overseas online pharmacies or obtained misoprostol from Mexico.<ref>Template:Cite news</ref>