今日の臨床サポート

頸管無力症

著者: 石本人士 東海大学 専門診療学系産婦人科学領域

監修: 金山尚裕 静岡医療科学専門大学校

著者校正/監修レビュー済:2022/09/14
参考ガイドライン:
  1. 日本産科婦人科学会/日本産婦人科医会:産婦人科診療ガイドライン産科編2020
  1. 米国産婦人科学会(ACOG):ACOG Practice Bulletin No.142: Cerclage for the management of cervical insufficiency (reaffirmed 2019)
  1. 英国国立医療技術評価機構(NICE): NICE guideline 25: Preterm labour (Nov 2015; Last updated: August 2, 2019)
患者向け説明資料

概要・推奨   

  1. 既往妊娠で頸管無力症と診断されるか強く疑われた場合、頸管の短縮や開大に注意しながら経過観察を行うか、あるいは予防的頸管縫縮術(妊娠12週以降のなるべく早期に実施)を行う(推奨度1 J)
  1. 経過観察中、妊娠24週までに頸管短縮を認めたら、治療的頸管縫縮術を行う(推奨度2 S/CS JG)
  1. 今回の妊娠で頸管無力症と診断された場合、切迫流早産に準じて注意深く経過観察を行うか、あるいは治療的頸管縫縮術を行う(推奨度1 J)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石本人士 : 特に申告事項無し[2022年]
監修:金山尚裕 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 主として産婦人科診療ガイドライン産科編2020に基づき、推奨根拠となる文献などにつき改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 頸管無力症は「妊娠16 週頃以後にみられる習慣流早産の原因のひとつである。外出血や子宮収縮などの、切迫流早産徴候を自覚しないにもかかわらず子宮口が開大し、胎胞が形成されてくる状態である」と、産科婦人科用語集・用語解説集(日本産科婦人科学会編、改訂新版、2003年)では記載されているものの、国内外において確立した疾患の定義や診断基準は存在しない。
  1. 正確な発生頻度は不明であるが、わが国では0.05~1%程度と推定されている。
  1. 妊娠20~22週前後に発症することが多い。
  1. 頸管の構造的・機能的脆弱性が病態の主体と考えられる。
  1. 流早産既往がなくとも、胎児異常や感染が明らかでないのに頸管長短縮・内子宮口開大傾向が明らかな場合は、初回妊娠であっても頸管無力症を疑う。
  1. ハイリスク群として、原因が明らかでない妊娠中期流早産既往例、子宮頸部円錐切除術既往例、頸管裂傷既往例などが挙げられる。<図表>
  1. 近年、明らかな頸管開大が生ずる以前の頸管変化(頸管長短縮や内子宮口開大など)を経腟超音波検査で捉えることが可能となり臨床応用されている。<図表>
  1. 一方で、頸管変化が早期に捉えられるようになったことで、本来の「頸管無力症」とそれ以外の原因で生じる流早産との区別が曖昧になってきている現状がある。
問診・診察と超音波検査のポイント  
問診:
  1. 頸管無力症や早産のリスク要因がないかどうかを確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

E R Guzman, C Mellon, A M Vintzileos, C V Ananth, C Walters, K Gipson
Longitudinal assessment of endocervical canal length between 15 and 24 weeks' gestation in women at risk for pregnancy loss or preterm birth.
Obstet Gynecol. 1998 Jul;92(1):31-7.
Abstract/Text OBJECTIVE: To determine the weekly cervical shortening rates of the endocervical canal between 15 and 24 weeks' gestation in women at risk for pregnancy loss or spontaneous preterm birth.
METHODS: We performed a retrospective cohort study of transvaginal sonographic measurements of the endocervical canal length done at least twice between 15 and 24 weeks' gestation in women at risk for pregnancy loss and spontaneous preterm birth. The ultrasound diagnosis of cervical incompetence was defined as progressive shortening of the endocervical canal length to 2 cm or less either spontaneously or after application of transfundal pressure. Multivariable linear regression models were developed to determine the weekly crude rate of endocervical canal length shortening rates in cases of competent cervices and incompetent cervices, with incompetent cervices further stratified as those diagnosed at 15-19 weeks' and 20-24 weeks' gestation. Comparisons of the models for weekly rate of endocervical canal length shortening were performed.
RESULTS: The endocervical canal lengths were measured in 61 women (180 measurements) who did not develop ultrasound evidence of cervical incompetence and 28 women (103 measurements) who had ultrasound evidence of cervical incompetence. Between 15 and 24 weeks' gestation, competent cervices had a nonsignificant rate of endocervical canal length shortening (-0.03 cm/week). During this period in gestation, incompetent cervices had significantly greater endocervical canal length shortening (-0.41 cm/week, P < .001). The rate of endocervical canal length shortening of incompetent cervices diagnosed between 15 and 19 weeks' gestation was -0.52 cm/week (P < .001). The rate of endocervical canal length shortening in incompetent cervices diagnosed between 20 and 24 weeks' gestation was significant and varied from -0.49 cm/week to -0.80 cm/week at 20 and 24 weeks' gestation, respectively (P < .001). The models describing the rate of cervical shortening in the two groups of incompetent cervices were significantly different (P < .001). The sonographic detection of endocervical canal length shortening in the 28 cases of cervical incompetence was identified at a median (range) gestational age of 20 (16-24) weeks.
CONCLUSION: Weekly rates of endocervical canal length shortening were established, which may be useful for detecting and managing cervical incompetence in high-risk women examined with cervical sonography.

PMID 9649088
Jennifer E Warren, Robert M Silver, Jess Dalton, Lesa T Nelson, D Ware Branch, T Flint Porter
Collagen 1Alpha1 and transforming growth factor-beta polymorphisms in women with cervical insufficiency.
Obstet Gynecol. 2007 Sep;110(3):619-24. doi: 10.1097/01.AOG.0000277261.92756.1a.
Abstract/Text OBJECTIVE: To estimate whether polymorphisms in the collagen 1Alpha1 gene (COL1Alpha1) and the transforming growth factor-beta gene (TGF-beta;1) are more common in women with cervical insufficiency than in those without the condition.
METHODS: Medical, obstetric, and family histories and blood were obtained from women with (n=121) and those without (n=165) cervical insufficiency. DNA was extracted and purified by using commercial DNA isolation kits. Samples were analyzed for variants in two genes, the COL1A1 intron 1SP1 and TGF-beta Arg-25-Pro polymorphism, by using an allele-specific polymerase chain reaction assay.
RESULTS: Thirty-four of 125 (27.2%) women with cervical insufficiency had at least one first-degree female relative affected. The frequency of the homozygous TT genotype in the COL1A1 gene was increased in women with a history of cervical insufficiency compared with controls (10.8% compared with 3.1%, P=.04). The TGF-beta polymorphisms (ArgPro and ProPro) also were increased in cases (38.3% compared with 14.6%, P<.001).
CONCLUSION: Over one fourth of women with cervical insufficiency have a family history of cervical insufficiency, and the COL1A1 intron 1SP1 and TGF-beta Arg-25-Pro polymorphisms are associated with the condition. These observations suggest that, in part, cervical insufficiency is mediated by genetic factors.
LEVEL OF EVIDENCE: II.

PMID 17766609
M Zilianti, A Azuaga, F Calderon, G Pagés, G Mendoza
Monitoring the effacement of the uterine cervix by transperineal sonography: a new perspective.
J Ultrasound Med. 1995 Oct;14(10):719-24.
Abstract/Text The objective of this study is to monitor the process of effacement of the uterine cervix and demonstrate that transperineal sonography is the appropriate technique for this purpose. Eighty-six patients with normal, term pregnancies were studied at the beginning of labor. Transperineal sonography was performed in transverse and longitudinal planes. After the initial examination, patients were reexamined several times during a 1 to 4 hour period. We observed a progressive shortening of the canal and the synchronous opening of a funnel-shaped internal cervical os. When the funneling process reached the lower end of the cervix, both orifices fused, completing the process of effacement. The dilatation of the external os, which remained stationary during initial phase, increases very quickly once the effacement has been completed. Transperineal sonography efficiently imaged the changes described here.

PMID 8544236
V Berghella, K Kuhlman, S Weiner, L Texeira, R J Wapner
Cervical funneling: sonographic criteria predictive of preterm delivery.
Ultrasound Obstet Gynecol. 1997 Sep;10(3):161-6. doi: 10.1046/j.1469-0705.1997.10030161.x.
Abstract/Text Our objective was to establish sonographic criteria that are predictive of preterm delivery in patients with internal os dilatation (funneling). The study population consisted of patients with cervical funneling identified on translabial or transvaginal ultrasound examination. Funnel length, functional length, percentage funneling and funnel width were evaluated for their predictive values for preterm delivery. In the 43 patients who met the study criteria, funneling was detected at a mean gestational age of 21.4 weeks (range 16-28). Twenty-three of 31 patients (74%), manually examined immediately following the ultrasound examination, had a closed cervix. Preterm delivery occurred in 42% of patients. Funnel length of > or = 16 mm, functional length of < or = 20 mm, funneling of > or = 40% and funnel width of > or = 14 mm correlated significantly with preterm delivery. Patients with funneling of < 25%, 25-50% and > 50% had preterm delivery rates of 17%, 29% and 79%, respectively.

PMID 9339522
J D Iams, R L Goldenberg, P J Meis, B M Mercer, A Moawad, A Das, E Thom, D McNellis, R L Copper, F Johnson, J M Roberts
The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
N Engl J Med. 1996 Feb 29;334(9):567-72. doi: 10.1056/NEJM199602293340904.
Abstract/Text BACKGROUND: The role of the cervix in the pathogenesis of premature delivery is controversial. In a prospective, multicenter study of pregnant women, we used vaginal ultrasonography to measure the length of the cervix; we also documented the incidence of spontaneous delivery before 35 weeks' gestation.
METHODS: At 10 university-affiliated prenatal clinics, we performed vaginal ultrasonography at approximately 24 and 28 weeks of gestation in women with singleton pregnancies. We then assessed the relation between the length of the cervix and the risk of spontaneous preterm delivery.
RESULTS: We examined 2915 women at approximately 24 weeks of gestation and 2531 of these women again at approximately 28 weeks. Spontaneous preterm delivery (at less than 35 weeks) occurred in 126 of the women (4.3 percent) examined at 24 weeks. The length of the cervix was normally distributed at 24 and 28 weeks (mean [+/- SD], 35.2 +/- 8.3 mm and 33.7 +/- 8.5 mm, respectively). The relative risk of preterm delivery increased as the length of the cervix decreased. When women with shorter cervixes at 24 weeks were compared with women with values above the 75th percentile, the relative risks of preterm delivery among the women with shorter cervixes were as follows: 1.98 for cervical lengths at or below the 75th percentile (40 mm), 2.35 for lengths at or below the 50th percentile (35 mm), 3.79 for lengths at or below the 25th percentile (30 mm), 6.19 for lengths at or below the 10th percentile (26 mm), 9.49 for lengths at or below the 5th percentile (22 mm), and 13.99 for lengths at or below the 1st percentile (13 mm) (P < 0.001 for values at or below the 50th percentile; P = 0.008 for values at or below the 75th percentile). For the lengths measured at 28 weeks, the corresponding relative risks were 2.80, 3.52, 5.39, 9.57, 13.88, and 24.94 (P < 0.001 for values at or below the 50th percentile; P = 0.003 for values at the 75th percentile).
CONCLUSIONS: The risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy.

PMID 8569824
Sietske M Althuisius, Gustaaf A Dekker, Pieter Hummel, Herman P van Geijn, Cervical incompetence prevention randomized cerclage trial
Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone.
Am J Obstet Gynecol. 2003 Oct;189(4):907-10.
Abstract/Text OBJECTIVE: The purpose of this study was to compare preterm delivery rates and neonatal morbidity/mortality rates for women with cervical incompetence with membranes at or beyond a dilated external cervical os that was treated with emergency cerclage, bed rest plus indomethacin, versus just bed rest.
STUDY DESIGN: Women with cervical incompetence with membranes at or beyond a dilated external cervical os, before 27 weeks of gestation, were treated with antibiotics and bed rest and randomly assigned for emergency cerclage and indomethacin or bed rest only.
RESULTS: Twenty-three women were included; 13 women were allocated randomly to the emergency cerclage and indomethacin group, and 10 women were allocated randomly to the bed rest-only group. Gestational age at time of randomization was 22.2 weeks in the emergency cerclage and indomethacin group and 23.0 weeks in the bed rest-only group. Mean interval from randomization until delivery was 54 days in the emergency cerclage and indomethacin group and 20 days in the bed rest-only group (P=.046). Mean gestational age at delivery was 29.9 weeks in the emergency cerclage and indomethacin group and 25.9 weeks in the bed rest-only group. Preterm delivery before 34 weeks of gestation was significantly lower in the emergency cerclage and indomethacin group, with 7 of 13 deliveries versus all 10 deliveries in the bed rest-only group (P=.02).
CONCLUSIONS: Emergency cerclage, indomethacin, antibiotics, and bed rest reduce preterm delivery before 34 weeks compared with bed rest and antibiotics alone.

PMID 14586323
R W Rush, S Isaacs, K McPherson, L Jones, I Chalmers, A Grant
A randomized controlled trial of cervical cerclage in women at high risk of spontaneous preterm delivery.
Br J Obstet Gynaecol. 1984 Aug;91(8):724-30.
Abstract/Text The effect of cervical suture on pregnancy outcome was studied in 194 women with a high risk (approximately 30%) of having a late abortion or a preterm delivery. The women were randomly allocated either to have a cervical suture inserted (n = 96) or to be managed without a suture (n = 98). There was no evidence that cervical cerclage either prolonged gestation or improved survival. Patients allocated to receive cerclage spent significantly longer in hospital, even when the period of admission for insertion was excluded. The patients in the cerclage group were more likely to receive tocolytic drugs, and more of them experienced puerperal pyrexia, although these differences between the groups were not statistically significant.

PMID 6380564
P Lazar, S Gueguen, J Dreyfus, R Renaud, G Pontonnier, E Papiernik
Multicentred controlled trial of cervical cerclage in women at moderate risk of preterm delivery.
Br J Obstet Gynaecol. 1984 Aug;91(8):731-5.
Abstract/Text A total of 506 women at moderate risk of preterm delivery were randomly allocated to either cervical cerclage or a control group. Significantly more women in the group allocated to cerclage were admitted to hospital for reasons other than the operation and more received oral tocolytic drugs. There were also more caesarean sections and more preterm deliveries in the women allocated to cerclage although the differences between the two groups were small and not statistically significant.

PMID 6380565
Abstract/Text OBJECTIVE: To assess whether cervical cerclage in women deemed to be at increased risk of cervical incompetence prolongs pregnancy and thereby improves fetal and neonatal outcome.
DESIGN: Multicentre randomised controlled trial.
SETTING: Hospitals in the United Kingdom, France, Hungary, Norway, Italy, Belgium, Zimbabwe, South Africa, Iceland, Ireland, the Netherlands and Canada.
SUBJECTS: One thousand two hundred and ninety-two pregnant women whose obstetricians were uncertain whether to recommend cervical cerclage, most of whom had a history of early delivery or cervical surgery.
INTERVENTIONS: Cervical cerclage was compared with a policy of withholding the operation unless it was considered to be clearly indicated.
MAIN OUTCOME MEASURES: Delivery before 33 completed weeks, preterm delivery (< 37 weeks), and vital status of the baby after completion of the pregnancy.
RESULTS: The overall preterm delivery rate was 28%. There were fewer deliveries before 33 weeks in the cerclage group (83 (13%) compared with 110 (17%), P = 0.03) and this difference reflected deliveries characterised by features of cervical incompetence (painless cervical dilatation and prelabour rupture of the membranes). There was a corresponding difference in very low birthweight deliveries (63 (10%) compared with 86 (13%), P = 0.05). The difference in the overall rate of miscarriage, stillbirth or neonatal death (55 (9%) compared with 68 (11%)) was less marked and was not statistically significant. The use of cervical cerclage was associated with increased medical intervention and a doubling of the risk of puerperal pyrexia.
CONCLUSIONS: These results suggest that the operation had an important beneficial effect in 1 in 25 cases in the trial (95% confidence interval (CI) 1 in 12 to 1 in 300 sutures). Its use is associated with increased medical intervention and puerperal pyrexia. Nevertheless, this trial suggests that, on balance, cervical cerclage should be offered to women at high risk, such as those with a history of three or more pregnancies ending before 37 weeks gestation.

PMID 8334085
Zarko Alfirevic, Tamara Stampalija, Devender Roberts, Andrea L Jorgensen
Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy.
Cochrane Database Syst Rev. 2012 Apr 18;4:CD008991. doi: 10.1002/14651858.CD008991.pub2. Epub 2012 Apr 18.
Abstract/Text BACKGROUND: Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give a mechanical support to the cervix and thereby reducing the risk of preterm birth. The effectiveness and safety of this procedure remains controversial.
OBJECTIVES: To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on a woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome.
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2011) and reference lists of identified studies.
SELECTION CRITERIA: We included all randomised trials of cervical suturing in singleton pregnancies carried out when pregnancy was considered to be at sufficiently high risk of pregnancy loss for cerclage to be potentially indicated. We included any study that compared cerclage with either no treatment or any alternative intervention.
DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. Data were checked for accuracy.
MAIN RESULTS: We included 12 trials (involving 3328 women). When cerclage was compared with no treatment, there was no statistically significant difference in perinatal deaths (8.4% versus 10.7%) (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.61 to 1.00; eight trials, 2391 women) and neonatal morbidity (9.6% versus 10.2%) (RR 0.95; 95% CI 0.63 to 1.43; four trials, 818 women), despite significant reduction in preterm births (average RR 0.80; 95% CI 0.69 to 0.95; nine trials, 2898 women). Cervical cerclage was associated with the higher rate of maternal side effects (vaginal discharge and bleeding, pyrexia) (average RR 2.25; 95% CI 0.89 to 5.69; three trials, 953 women). Caesarean section rates were significantly higher after cervical cerclage (RR 1.19; 95% CI 1.01 to 1.40; 8 trials, 2817 women).There was no evidence of any important differences across all prespecified clinical subgroups (history-indicated, ultrasound-indicated)One study that compared cerclage with weekly intramuscular injections of 17 α-hydroxyprogesterone caproate in women with a short cervix detected by transvaginal ultrasound, failed to reveal any obvious differences in obstetric and neonatal outcomes between the two management strategies.Two studies compared the benefits of performing cerclage based on previous history with cerclage, only if the cervix was found to be short on transvaginal ultrasound. There was no significant difference in any of the primary and secondary outcomes.
AUTHORS' CONCLUSIONS: Compared with no treatment, cervical cerclage reduces the incidence of preterm birth in women at risk of recurrent preterm birth without statistically significant reduction in perinatal mortality or neonatal morbidity and uncertain long-term impact on the baby. Ceasarean section is more likely in women who had cervical suture inserted during pregnancy.The decision on how best to minimise the risk of recurrent preterm birth in women at risk, either because of poor history of a short or dilated cervix, should be 'personalised', based on the clinical circumstances, the skill and expertise of the clinical team and, most importantly, woman's informed choice.

PMID 22513970
Vincenzo Berghella, A Dhanya Mackeen
Cervical length screening with ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth: a meta-analysis.
Obstet Gynecol. 2011 Jul;118(1):148-55. doi: 10.1097/AOG.0b013e31821fd5b0.
Abstract/Text OBJECTIVE: To compare pregnancy outcomes in singleton gestations with prior preterm birth that were managed either by cervical length screening with cerclage for short cervical length or history-indicated cerclage. DATA SOURCES AND METHODS OF STUDY SELECTION: Medline, Scopus, and the Cochrane Central Register of Controlled Trials were searched for the terms "cerclage," "randomized trial," and "clinical trial" from 1966 until January 2011. No restrictions for language were applied. We performed a meta-analysis of randomized trials of singleton gestations with prior preterm birth. Management by policy of transvaginal ultrasonography cervical length screening with cerclage placement for cervical shortening was compared with history-indicated cerclage.
TABULATION, INTEGRATION, AND RESULTS: Four randomized trials met inclusion criteria, including 467 women. In women with a singleton gestation and prior preterm birth, cervical length screening with cerclage for short cervical length was associated with similar incidences of preterm birth before 37 weeks (31% compared with 32%, relative risk 0.97, 95% confidence interval [CI] 0.73-1.29), preterm birth before 34 weeks (17% compared with 23%, relative risk 0.76, 95% CI 0.48-1.20), and perinatal mortality (5% compared with 3%, relative risk 1.77, 95% CI 0.58-5.35) compared with history-indicated cerclage. In the transvaginal ultrasound cervical length screening group, 42% developed a short cervical length and received cerclage.
CONCLUSION: Singleton gestations in women with prior preterm birth may be monitored safely with a policy of transvaginal ultrasound cervical length screening as compared with a policy of routine history-indicated cerclage. Cerclage can be reserved for the minority of women who develop a short cervical length.

PMID 21691173
John Owen, Gary Hankins, Jay D Iams, Vincenzo Berghella, Jeanne S Sheffield, Annette Perez-Delboy, Robert S Egerman, Deborah A Wing, Mark Tomlinson, Richard Silver, Susan M Ramin, Edwin R Guzman, Michael Gordon, Helen Y How, Eric J Knudtson, Jeff M Szychowski, Suzanne Cliver, John C Hauth
Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length.
Am J Obstet Gynecol. 2009 Oct;201(4):375.e1-8. doi: 10.1016/j.ajog.2009.08.015.
Abstract/Text OBJECTIVE: The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix.
STUDY DESIGN: Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm.
RESULTS: Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks (P = .09). In planned analyses, birth less than 24 weeks (P = .03) and perinatal mortality (P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks (P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum.
CONCLUSION: In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm.

PMID 19788970
Vincenzo Berghella, Timothy J Rafael, Jeff M Szychowski, Orion A Rust, John Owen
Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis.
Obstet Gynecol. 2011 Mar;117(3):663-71.
Abstract/Text OBJECTIVE: To estimate if cerclage prevents preterm birth and perinatal mortality and morbidity in women with previous preterm birth, singleton gestation, and short cervical length in a meta-analysis of randomized trials.
DATA SOURCES: MEDLINE, PUBMED, EMBASE, and the Cochrane Library were searched using the terms "cerclage," "short cervix," "ultrasound," and "randomized trial."
METHODS OF STUDY SELECTION: We included randomized trials of cerclage in women with short cervical length on transvaginal ultrasonography, limiting the analysis to women with previous spontaneous preterm birth and singleton gestation.
TABULATION, INTEGRATION, AND RESULTS: Patient-level data abstraction and analysis were accomplished by two independent investigators. Five trials met inclusion criteria. In women with a singleton gestation, previous spontaneous preterm birth, and cervical length less than 25 mm before 24 weeks of gestation, preterm birth before 35 weeks of gestation was 28.4% (71/250) in the cerclage compared with 41.3% (105/254) in the no cerclage groups (relative risk 0.70, 95% confidence interval 0.55– 0.89). Cerclage also significantly reduced preterm birth before 37, 32, 28, and 24 weeks of gestation. Composite perinatal mortality and morbidity were significantly reduced (15.6% in cerclage compared with 24.8% in no cerclage groups; relative risk 0.64, 95% confidence interval 0.45– 0.91).
CONCLUSION: In women with previous spontaneous preterm birth, singleton gestation, and cervical length less than 25 mm, cerclage significantly prevents preterm birth and composite perinatal mortality and morbidity.

PMID 21446209
Anju Suhag, Neil S Seligman, Ilaria Bianchi, Vincenzo Berghella
What is the optimal gestational age for history-indicated cerclage placement?
Am J Perinatol. 2010 Jun;27(6):469-74. doi: 10.1055/s-0030-1247601. Epub 2010 Jan 29.
Abstract/Text We estimated the optimal gestational age for placement of a history-indicated cerclage in a retrospective cohort study of pregnancies during the period between 1994 to 2007. Pregnancies were divided into two groups: group 1, cerclage <14 weeks (N = 83), and group 2, cerclage >or=14 weeks (N = 59). The primary outcome was spontaneous preterm birth (SPTB) <35 weeks. Parametric and nonparametric tests were performed where appropriate. One hundred forty-two pregnancies by 130 women were included. Demographic characteristics were similar between groups. The median gestational age at cerclage was 12 weeks (group 1) and 15 weeks (group 2). There was no difference in the primary outcome, incidence of SPTB <35 weeks (17% versus 20%; P = 0.59) between groups 1 and 2, respectively. Likewise, the secondary outcomes, mean gestational age at birth (38 versus 37 weeks; P = 0.96), incidence of low birth weight (28% versus 23%; P = 0.50), and the incidence of preterm premature rupture of membranes (17% versus 18%; P = 0.89) were similar between groups. No other gestational age cutoff was predictive of SPTB <35 weeks using a receiver operator characteristic curve (13 to 17 weeks; area = 0.52; P = 0.64). Gestational age of history-indicated cerclage placement was not associated with a significant effect on preterm birth in high-risk women. The optimal gestational age for placement of a history-indicated cerclage is probably 12 to 14 weeks, after screening for fetal anomalies and aneuploidy.

Thieme Medical Publishers.
PMID 20119889
Robert M Ehsanipoor, Neil S Seligman, Gabriele Saccone, Linda M Szymanski, Christina Wissinger, Erika F Werner, Vincenzo Berghella
Physical Examination-Indicated Cerclage: A Systematic Review and Meta-analysis.
Obstet Gynecol. 2015 Jul;126(1):125-35. doi: 10.1097/AOG.0000000000000850.
Abstract/Text OBJECTIVE: To estimate the effectiveness of physical examination-indicated cerclage in the setting of second-trimester cervical dilatation by systematic review and meta-analysis of published studies.
DATA SOURCES: We searched MEDLINE, EMBASE, Scopus, ClinicalTrials.gov, Web of Science, and the Cochrane Library for studies published between 1966 and 2014 that evaluated cervical cerclage for the treatment of cervical insufficiency.
METHODS OF STUDY SELECTION: The search yielded 6,314 citations. We included cohort studies and randomized controlled trials comparing cerclage placement with expectant management of women with cervical dilatation between 14 and 27 weeks of gestation. Two investigators independently reviewed each citation for inclusion or exclusion and discordant decisions were arbitrated by a third reviewer. Summary estimates were reported as the mean difference and 95% confidence interval (CI) for continuous variables or relative risk and with 95% CI for dichotomous outcomes. Fixed- and random-effects meta-analysis was used, depending on heterogeneity.
TABULATION, INTEGRATION, AND RESULTS: Ten studies met inclusion criteria and were included in the final analysis. One was a randomized controlled trial, two were prospective cohort studies, and the remaining seven were retrospective cohort studies. Of the 757 women, 485 (64%) underwent physical examination-indicated cerclage placement and 272 (36%) were expectantly managed. Cerclage was associated with increased neonatal survival (71% compared with 43%; relative risk 1.65, 95% CI 1.19-2.28) and prolongation of pregnancy (mean difference 33.98 days, 95% CI 17.88-50.08).
CONCLUSION: Physical examination-indicated cerclage is associated with a significant increase in neonatal survival and prolongation of pregnancy of approximately 1 month when compared with no such cerclage. The strength of this conclusion is limited by the potential for bias in the included studies.

PMID 26241265
Shigeru Aoki, Emi Ohnuma, Kentaro Kurasawa, Mika Okuda, Tsuneo Takahashi, Fumiki Hirahara
Emergency cerclage versus expectant management for prolapsed fetal membranes: a retrospective, comparative study.
J Obstet Gynaecol Res. 2014 Feb;40(2):381-6. doi: 10.1111/jog.12207. Epub 2013 Oct 22.
Abstract/Text AIM: To compare outcomes after emergency cerclage versus expectant management for prolapsed fetal membranes in women with cervical incompetency.
METHODS: The January 2000-December 2012 hospital database was analyzed to identify women managed for prolapsed fetal membranes who did not have premature rupture of membranes, clinically discernible chorioamnionitis, or treatment-resistant uterine contractions from 15 to 26 weeks of gestation retrospectively. Durations of pregnancy prolongation and numbers of deliveries after 32 and 28 weeks were compared between women undergoing emergency cervical cerclage and those receiving expectant management.
RESULTS: Fifteen of the 35 women underwent emergency cervical cerclage ('cerclage group'), while the other 20 were managed expectantly ('bedrest group'). In the cerclage group, median gestational ages at procedure and delivery times were 22.6 (15.9-26.1) and 32.4 (19.4-41.6) weeks, respectively. Median gestational ages on admission and at delivery in the bedrest group were 23.4 (21.1-26.4) and 26.0 (23.1-36.4) weeks, respectively. The median duration of pregnancy prolongation was 44 days (4-165) in the cerclage group and 12.5 days (2-93) in the bedrest group (P < 0.01). Numbers of deliveries after 28 and 32 weeks were both significantly higher in the cerclage than in the bedrest group (P < 0.05).
CONCLUSION: In women with prolapsed fetal membranes but no signs of infection or painful uterine contractions, emergency cervical cerclage prolonged pregnancy duration as compared with expectant management.

© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.
PMID 24147884
Meekai S To, Zarko Alfirevic, Victoria C F Heath, Simona Cicero, Ana Maria Cacho, Paula R Williamson, Kypros H Nicolaides, Fetal Medicine Foundation Second Trimester Screening Group
Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
Lancet. 2004 Jun 5;363(9424):1849-53. doi: 10.1016/S0140-6736(04)16351-4.
Abstract/Text BACKGROUND: Cervical cerclage has been widely used in the past 50 years to prevent early preterm birth and its associated neonatal mortality and morbidity. Results of randomised trials have not generally lent support to this practice, but this absence of benefit may be due to suboptimum patient selection, which was essentially based on obstetric history. A more effective way of identifying the high-risk group for early preterm delivery might be by transvaginal sonographic measurement of cervical length. We undertook a multicentre randomised controlled trial to investigate whether, in women with a short cervix identified by routine transvaginal scanning at 22-24 weeks' gestation, the insertion of a Shirodkar suture reduces early preterm delivery.
METHODS: Cervical length was measured in 47?123 women. The cervix was 15 mm or less in 470, and 253 (54%) of these women participated in the study and were randomised to cervical cerclage (127) or to expectant management (126). Primary outcome was the frequency of delivery before 33 completed weeks (231 days) of pregnancy.
FINDINGS: The proportion of preterm delivery before 33 weeks was similar in both groups, 22% (28 of 127) in the cerclage group versus 26% (33 of 126) in the control group (relative risk=0.84, 95% CI 0.54-1.31, p=0.44), with no significant differences in perinatal or maternal morbidity or mortality.
INTERPRETATION: The insertion of a Shirodkar suture in women with a short cervix does not substantially reduce the risk of early preterm delivery. Routine sonographic measurement of cervical length at 22-24 weeks identifies a group at high risk of early preterm birth.

PMID 15183621
Katsufumi Otsuki, Akihito Nakai, Yoshio Matsuda, Norio Shinozuka, Ikuno Kawabata, Yasuo Makino, Yoshimasa Kamei, Mitsutoshi Iwashita, Takashi Okai
Randomized trial of ultrasound-indicated cerclage in singleton women without lower genital tract inflammation.
J Obstet Gynaecol Res. 2016 Feb;42(2):148-57. doi: 10.1111/jog.12880. Epub 2015 Dec 3.
Abstract/Text AIM: This is the first report of a randomized trial of cerclage on pure cervical shortening without vaginosis or cervicitis. The objective of our multicenter randomized controlled trial was to assess the benefits of ultrasound-indicated cervical cerclage in the mid-trimester to prevent preterm birth in women who have no signs of infection or inflammation of the lower genital tract.
MATERIAL AND METHODS: Women with a short cervical length < 25 mm between 16 and 26 weeks of gestation were randomly assigned to receive a Shirodkar cerclage, McDonald cerclage, or bedrest (no cerclage). Before being randomly assigned to one of the three groups, all women were screened for infection/inflammation of the lower genital tract; those with positive results were excluded from the study. The ratio of preterm delivery as a primary end-point was evaluated in the groups.
RESULTS: A total of 106 singleton patients with a short cervical length were assessed for study eligibility; 106 patients were randomized to the three treatment options. Ultimately, 98 patients (in the Shirodkar [n = 34], McDonald [n = 34] and bedrest [n = 30] groups) were analyzed. No differences in preterm delivery or perinatal outcomes were found between the three groups. Significantly fewer patients in the Shirodkar group required hospitalization for treatment of threatened preterm labor when compared to patients in the bedrest group.
CONCLUSION: For women with a short cervical length < 25 mm between 16 and 26 weeks of gestation, Shirodkar cerclage might be considered to reduce the occurrence of threatened preterm labor.

© 2015 Japan Society of Obstetrics and Gynecology.
PMID 26633738
V Berghella, A Ciardulli, O A Rust, M To, K Otsuki, S Althuisius, K H Nicolaides, A Roman, G Saccone
Cerclage for sonographic short cervix in singleton gestations without prior spontaneous preterm birth: systematic review and meta-analysis of randomized controlled trials using individual patient-level data.
Ultrasound Obstet Gynecol. 2017 Nov;50(5):569-577. doi: 10.1002/uog.17457. Epub 2017 Oct 5.
Abstract/Text OBJECTIVE: The aim of this systematic review and meta-analysis was to quantify the efficacy of cervical cerclage in preventing preterm birth (PTB) in asymptomatic singleton pregnancies with a short mid-trimester cervical length (CL) on transvaginal sonography (TVS) and without prior spontaneous PTB.
METHODS: Electronic databases were searched from inception of each database until February 2017. No language restrictions were applied. All randomized controlled trials (RCTs) of asymptomatic singleton pregnancies without prior spontaneous PTB, found to have short CL < 25 mm on mid-trimester TVS and then randomized to management with either cerclage or no cerclage, were included. Corresponding authors of all the included trials were contacted to obtain access to the data and perform a meta-analysis of individual patient-level data. Data provided by the investigators were merged into a master database constructed specifically for the review. Primary outcome was PTB < 35 weeks. Summary measures were reported as relative risk (RR) with 95% CI. The quality of the evidence was assessed using the GRADE approach.
RESULTS: Five RCTs, including 419 asymptomatic singleton gestations with TVS-CL < 25 mm and without prior spontaneous PTB, were analyzed. In women who were randomized to the cerclage group compared with those in the control group, no statistically significant differences were found in PTB < 35 (21.9% vs 27.7%; RR, 0.88 (95% CI 0.63-1.23); I2  = 0%; five studies, 419 participants), < 34, < 32, < 28 and < 24 weeks, gestational age at delivery, preterm prelabor rupture of membranes (PPROM) and neonatal outcomes. In women who received cerclage compared with those who did not, planned subgroup analyses revealed a significantly lower rate of PTB < 35 weeks in women with TVS-CL < 10 mm (39.5% vs 58.0%; RR, 0.68 (95% CI, 0.47-0.98); I2  = 0%; five studies; 126 participants) and in women who received tocolytics (17.5% vs 32.7%; RR, 0.54 (95% CI, 0.31-0.93); I2  = 0%; four studies; 169 participants) or antibiotics (18.3% vs 31.5%; RR, 0.58 (95% CI, 0.33-0.98); I2  = 0%; three studies; 163 participants) as additional therapy to cerclage. The quality of evidence was downgraded two levels because of serious imprecision and indirectness, and therefore was judged as low.
CONCLUSIONS: In singleton gestations without prior spontaneous PTB but with TVS-CL < 25 mm in the second trimester, cerclage does not seem to prevent preterm delivery or improve neonatal outcome. However, in these pregnancies, cerclage seems to be efficacious at lower CLs, such as < 10 mm, and when tocolytics or antibiotics are used as additional therapy, requiring further studies in these subgroups. Given the low quality of evidence, further well-designed RCTs are needed to confirm the findings of this study. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
PMID 28295722
Masatoshi Sakai, Arihiro Shiozaki, Mika Tabata, Yasushi Sasaki, Satoshi Yoneda, Takashi Arai, Kiyoshi Kato, Yoshihiro Yamakawa, Shigeru Saito
Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus.
Am J Obstet Gynecol. 2006 Jan;194(1):14-9. doi: 10.1016/j.ajog.2005.06.014.
Abstract/Text OBJECTIVE: This study was undertaken to compare rates of preterm delivery according to cervical mucus interleukin-8 (IL-8) among women who underwent cerclage because of a short cervix.
STUDY DESIGN: This retrospective study included 16,508 patients whose cervical length and cervical mucus IL-8 concentrations were measured between 20 and 24 weeks. A short cervix was defined by a length of 25 mm or less, whereas IL-8 concentrations exceeding 360 ng/mL were considered high. Whether to perform cerclage was decided by clinicians without consideration of IL-8 concentrations.
RESULTS: Among all subjects, a significantly smaller percentage of subjects avoided delivery before 37 weeks when cervical mucus IL-8 was elevated (P = .0302) or the cervix was short (P < .0001). Among patients with a short cervix, preterm delivery was more likely when cervical mucus IL-8 was elevated. Overall, risk of preterm delivery in patients with a short cervix did not differ between those undergoing and not undergoing cerclage. However, among patients with a short cervix, those with normal IL-8 concentrations in cervical mucus were less likely to have preterm delivery if they underwent cerclage (before 37 weeks, 33% vs 54.5%, P = .01; before 34 weeks, 4% vs 13.6%, P = .03). In contrast, when cervical mucus IL-8 was high, delivery before 37 weeks was more likely with than without cerclage (78% vs 54.1%, P = .03).
CONCLUSION: With normal cervical mucus IL-8, cerclage treatment for cervical shortening may reduce the rate of preterm delivery, but with elevated cervical mucus IL-8 cerclage may be harmful.

PMID 16389005
H Minakami, S Matsubara, A Izumi, S Kosuge, T Watanabe, R Iwasaki, I Sato
Emergency cervical cerclage: relation between its success, preoperative serum level of C-reactive protein and WBC count, and degree of cervical dilatation.
Gynecol Obstet Invest. 1999;47(3):157-61. doi: 10084.
Abstract/Text OBJECTIVE: To assess the relation between the preoperative serum level of C-reactive protein (CRP) and the WBC count and the efficacy of emergency cervical cerclage.
STUDY DESIGN: We retrospectively reviewed the medical records of 17 women (16 singleton pregnancies and 1 twin pregnancy) who underwent emergency cervical cerclage (McDonald technique) between 21 and 26 weeks of gestation. The uterine cervix was dilated >/=3.0 cm and the intact (not ruptured) fetal membranes were visible or protruded into the vagina in all patients. The serum level of CRP and the WBC count were determined preoperatively and postoperatively. Emergency cervical cerclage was considered successful if delivery occurred >/=14 days after the procedure.
RESULTS: Emergency cervical cerclage was successful in 12 women, including the woman with a twin pregnancy, but failed in 5 women. The preoperative serum level of CRP and the WBC count were significantly lower and dilatation of the cervix was significantly less in the success group than in the failure group. Cerclage was successful in all eight patients with cervical dilatation 4.0 cm (p < 0. 05). Cerclage was successful in all 11 women with a preoperative serum level of CRP 4.0 mg/dl or a WBC count >14,000/ microl (p < 0.01).
CONCLUSION: A preoperative CRP value
PMID 10087408
Mami Kobayashi, Akihide Ohkuchi, Shigeki Matsubara, Akio Izumi, Chikako Hirashima, Mitsuaki Suzuki
C-reactive protein levels at pre-/post-indicated cervical cerclage predict very preterm birth.
J Perinat Med. 2011 Mar;39(2):151-5. doi: 10.1515/JPM.2011.003. Epub 2011 Feb 10.
Abstract/Text AIMS: To investigate the relation between serum levels of C-reactive protein (CRP) at pre-/post-cerclage points and preterm birth at <33 weeks of gestation in women with indicated cervical cerclage (CC).
METHODS: Fifty-eight women with CC indicated for a short or soft cervix, but no visible or protruding fetal membranes into the vagina, between 17 and 26 weeks of gestation, were reviewed. Serum CRP levels were examined three times: just before cerclage, and on day 1 and day 2 post-cerclage.
RESULTS: Serum CRP levels on day 1 and day 2, but not just before cerclage, predicted the occurrence of very preterm birth. In women with cervical dilatation of <3.0 cm, serum CRP levels on post-cerclage day 1 were associated with the increase of very preterm birth [CRP ≥1.5 mg/dL vs. <1.5 mg/dL: 4/5 (80%) vs. 8/31 (26%), P=0.033]. In women with cervical dilatation of <3.0 cm, serum CRP ≥3.0 mg/dL on post-cerclage day 2 was also associated with the increase of very preterm birth.
CONCLUSION: In women with indicated CC between 17 and 26 weeks of gestation, increased levels of serum CRP on post-cerclage day 1 or 2 might be ominous signs for very preterm birth.

PMID 21309632
Eduardo B Fonseca, Ebru Celik, Mauro Parra, Mandeep Singh, Kypros H Nicolaides, Fetal Medicine Foundation Second Trimester Screening Group
Progesterone and the risk of preterm birth among women with a short cervix.
N Engl J Med. 2007 Aug 2;357(5):462-9. doi: 10.1056/NEJMoa067815.
Abstract/Text BACKGROUND: Previous randomized trials have shown that progesterone administration in women who previously delivered prematurely reduces the risk of recurrent premature delivery. Asymptomatic women found at midgestation to have a short cervix are at greatly increased risk for spontaneous early preterm delivery, and it is unknown whether progesterone reduces this risk in such women.
METHODS: Cervical length was measured by transvaginal ultrasonography at a median of 22 weeks of gestation (range, 20 to 25) in 24,620 pregnant women seen for routine prenatal care. Cervical length was 15 mm or less in 413 of the women (1.7%), and 250 (60.5%) of these 413 women were randomly assigned to receive vaginal progesterone (200 mg each night) or placebo from 24 to 34 weeks of gestation. The primary outcome was spontaneous delivery before 34 weeks.
RESULTS: Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; relative risk, 0.56; 95% confidence interval [CI], 0.36 to 0.86). Progesterone was associated with a nonsignificant reduction in neonatal morbidity (8.1% vs. 13.8%; relative risk, 0.59; 95% CI, 0.26 to 1.25; P=0.17). There were no serious adverse events associated with the use of progesterone.
CONCLUSIONS: In women with a short cervix, treatment with progesterone reduces the rate of spontaneous early preterm delivery. (ClinicalTrials.gov number, NCT00422526 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17671254
Roberto Romero, Agustin Conde-Agudelo, Eduardo Da Fonseca, John M O'Brien, Elcin Cetingoz, George W Creasy, Sonia S Hassan, Kypros H Nicolaides
Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
Am J Obstet Gynecol. 2018 Feb;218(2):161-180. doi: 10.1016/j.ajog.2017.11.576. Epub 2017 Nov 17.
Abstract/Text BACKGROUND: The efficacy of vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix has been questioned after publication of the OPPTIMUM study.
OBJECTIVE: To determine whether vaginal progesterone prevents preterm birth and improves perinatal outcomes in asymptomatic women with a singleton gestation and a midtrimester sonographic short cervix.
STUDY DESIGN: We searched MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to September 2017); Cochrane databases; bibliographies; and conference proceedings for randomized controlled trials comparing vaginal progesterone vs placebo/no treatment in women with a singleton gestation and a midtrimester sonographic cervical length ≤25 mm. This was a systematic review and meta-analysis of individual patient data. The primary outcome was preterm birth <33 weeks of gestation. Secondary outcomes included adverse perinatal outcomes and neurodevelopmental and health outcomes at 2 years of age. Individual patient data were analyzed using a 2-stage approach. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology.
RESULTS: Data were available from 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length ≤25 mm participating in 5 high-quality trials. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95% confidence interval, 0.47-0.81; P = .0006; high-quality evidence). Moreover, vaginal progesterone significantly decreased the risk of preterm birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (relative risks from 0.47-0.82; high-quality evidence for all). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (relative risk, 0.44; 95% confidence interval, 0.18-1.07; P = .07; low-quality evidence). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups.
CONCLUSION: Vaginal progesterone decreases the risk of preterm birth and improves perinatal outcomes in singleton gestations with a midtrimester sonographic short cervix, without any demonstrable deleterious effects on childhood neurodevelopment.

Published by Elsevier Inc.
PMID 29157866
Jane Elizabeth Norman, Neil Marlow, Claudia-Martina Messow, Andrew Shennan, Phillip R Bennett, Steven Thornton, Stephen C Robson, Alex McConnachie, Stavros Petrou, Neil J Sebire, Tina Lavender, Sonia Whyte, John Norrie, OPPTIMUM study group
Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
Lancet. 2016 May 21;387(10033):2106-2116. doi: 10.1016/S0140-6736(16)00350-0. Epub 2016 Feb 24.
Abstract/Text BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.
METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.
FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).
INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.
FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Copyright © 2016 Norman et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
PMID 26921136
Agustin Conde-Agudelo, Roberto Romero, Eduardo Da Fonseca, John M O'Brien, Elcin Cetingoz, George W Creasy, Sonia S Hassan, Offer Erez, Percy Pacora, Kypros H Nicolaides
Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis.
Am J Obstet Gynecol. 2018 Jul;219(1):10-25. doi: 10.1016/j.ajog.2018.03.028. Epub 2018 Apr 7.
Abstract/Text BACKGROUND: An indirect comparison meta-analysis published in 2013 reported that both vaginal progesterone and cerclage are equally efficacious for preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic short cervix. The efficacy of vaginal progesterone has been challenged after publication of the OPPTIMUM study. However, this has been resolved by an individual patient-data meta-analysis (Am J Obstet Gynecol. 2018;218:161-180).
OBJECTIVE: To compare the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix.
DATA SOURCES: MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to March 2018); Cochrane databases, bibliographies, and conference proceedings.
STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic cervical length <25 mm.
STUDY APPRAISAL AND SYNTHESIS METHODS: Updated systematic review and adjusted indirect comparison meta-analysis of vaginal progesterone vs cerclage using placebo/no cerclage as the common comparator. The primary outcomes were preterm birth <35 weeks of gestation and perinatal mortality. Pooled relative risks (RRs) with 95% confidence intervals were calculated.
RESULTS: Five trials comparing vaginal progesterone vs placebo (265 women) and 5 comparing cerclage vs no cerclage (504 women) were included. Vaginal progesterone, compared to placebo, significantly reduced the risk of preterm birth <35 and <32 weeks of gestation, composite perinatal morbidity/mortality, neonatal sepsis, composite neonatal morbidity, and admission to the neonatal intensive care unit (RRs from 0.29 to 0.68). Cerclage, compared to no cerclage, significantly decreased the risk of preterm birth <37, <35, <32, and <28 weeks of gestation, composite perinatal morbidity/mortality, and birthweight <1500 g (RRs from 0.64 to 0.70). Adjusted indirect comparison meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes.
CONCLUSION: Vaginal progesterone and cerclage are equally effective for preventing preterm birth and improving perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. The choice of treatment will depend on adverse events and cost-effectiveness of interventions and patient/physician's preferences.

Published by Elsevier Inc.
PMID 29630885
William A Grobman, Elizabeth A Thom, Catherine Y Spong, Jay D Iams, George R Saade, Brian M Mercer, Alan T N Tita, Dwight J Rouse, Yoram Sorokin, Ronald J Wapner, Kenneth J Leveno, Sean Blackwell, M Sean Esplin, Jorge E Tolosa, John M Thorp, Steve N Caritis, J Peter Van Dorsten, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network
17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.
Am J Obstet Gynecol. 2012 Nov;207(5):390.e1-8. doi: 10.1016/j.ajog.2012.09.013. Epub 2012 Sep 17.
Abstract/Text OBJECTIVE: We sought to evaluate whether 17 alpha-hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL) <30 mm.
STUDY DESIGN: In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL <30 mm (<10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB <37 weeks.
RESULTS: The frequency of PTB did not differ between the 17-OHP (n = 327) and placebo (n = 330) groups (25.1% vs 24.2%; relative risk, 1.03; 95% confidence interval, 0.79-1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs 9.1%; relative risk, 0.77; 95% confidence interval, 0.46-1.30).
CONCLUSION: Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL <30 mm.

Copyright © 2012 Mosby, Inc. All rights reserved.
PMID 23010094
Paul J Meis, Mark Klebanoff, Elizabeth Thom, Mitchell P Dombrowski, Baha Sibai, Atef H Moawad, Catherine Y Spong, John C Hauth, Menachem Miodovnik, Michael W Varner, Kenneth J Leveno, Steve N Caritis, Jay D Iams, Ronald J Wapner, Deborah Conway, Mary J O'Sullivan, Marshall Carpenter, Brian Mercer, Susan M Ramin, John M Thorp, Alan M Peaceman, Steven Gabbe, National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
N Engl J Med. 2003 Jun 12;348(24):2379-85. doi: 10.1056/NEJMoa035140.
Abstract/Text BACKGROUND: Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery.
METHODS: We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle.
RESULTS: Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen.
CONCLUSIONS: Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.

Copyright 2003 Massachusetts Medical Society
PMID 12802023
Catherine Y Spong, Paul J Meis, Elizabeth A Thom, Baha Sibai, Mitchell P Dombrowski, Atef H Moawad, John C Hauth, Jay D Iams, Michael W Varner, Steve N Caritis, Mary J O'Sullivan, Menachem Miodovnik, Kenneth J Leveno, Deborah Conway, Ronald J Wapner, Marshall Carpenter, Brian Mercer, Susan M Ramin, John M Thorp, Alan M Peaceman, Steven Gabbe, National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network
Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery.
Am J Obstet Gynecol. 2005 Sep;193(3 Pt 2):1127-31. doi: 10.1016/j.ajog.2005.05.077.
Abstract/Text OBJECTIVE: Preterm birth occurs in 1 of 8 pregnancies and may result in significant morbidity and mortality. 17-alpha hydroxyprogesterone caproate (17-OHP caproate) has been found to be efficacious in reducing the risk of subsequent preterm delivery in women who have had a previous spontaneous preterm birth (sPTB). This analysis was undertaken to evaluate if 17-OHP caproate therapy works preferentially depending on the gestational age at previous spontaneous delivery. We hypothesized that treatment with 17-OHP caproate is more effective in prolonging pregnancy depending on the gestational age of the earliest previous preterm birth (20-27.9, 28-33.9 vs 34-36.9 weeks).
STUDY DESIGN: This was a secondary analysis of 459 women with a previous sPTB enrolled in a randomized controlled trial evaluating 17-OHP caproate versus placebo. Effectiveness of 17-OHP caproate for pregnancy prolongation was evaluated based on gestational age at earliest previous delivery according to clinically relevant groupings (20-27.9, 28-33.9, and 34-36.9 weeks). Statistical analysis included the chi-square, Fisher exact, and Kruskal-Wallis tests, logistic regression, and survival analysis using proportional hazards.
RESULTS: Gestational age at earliest previous delivery was similar between women treated with 17-OHP caproate or placebo (P = .1). Women with earliest delivery at 20 to 27.9 weeks and at 28 to 33.9 weeks delivered at significantly more advanced gestational age if treated with 17-OHP caproate than with placebo (median 37.3 vs 35.4 weeks, P = .046 and 38.0 vs 36.7 weeks, P = .004, respectively) and were less likely to deliver <37 weeks (42% vs 63%, P = .026 and 34% vs 56%, P = .005, respectively). Those with earliest delivery at 34 to 36.9 weeks were not significantly different between 17-OHP caproate or control.
CONCLUSION: 17-OHP caproate therapy given to prevent recurrent PTB is associated with a prolongation of pregnancy overall, and especially for women with a previous spontaneous PTB at <34 weeks.

PMID 16157124
Mohammad Ahmed Maher, Ahmed Abdelaziz, Mohamed Ellaithy, Mohamed Fayez Bazeed
Prevention of preterm birth: a randomized trial of vaginal compared with intramuscular progesterone.
Acta Obstet Gynecol Scand. 2013 Feb;92(2):215-22. doi: 10.1111/aogs.12017. Epub 2012 Dec 5.
Abstract/Text OBJECTIVE: To assess efficacy and tolerability of vaginal compared with intramuscular progesterone in reducing the rate of recurrent preterm birth before 34 weeks of gestation.
DESIGN: Prospective randomized study.
SETTING: Obstetrics and Gynecology Department, Armed Forces Hospital Southern Region, Kingdom of Saudi Arabia.
SAMPLE: Five-hundred and eighteen women with a prior history of preterm birth.
METHODS: Women were randomized to receive either 90 mg of vaginal progesterone gel once daily or 250 mg of intramuscular progesterone weekly. Treatment began between 14 and 18 weeks of gestation and continued until 36 complete weeks of gestation, delivery or the occurrence of premature rupture of membranes.
MAIN OUTCOME MEASURES: The primary outcome measure was delivery before 34 weeks of gestation. The secondary outcome measures were PTB between 34 and 37 weeks of gestation and neonatal outcomes including birthweight, neonatal death, and the need for admission to the neonatal intensive care unit.
RESULTS: The baseline characteristics of the study participants were similar. Two-hundred and thirty-eight (94.1%) patients in the vaginal group and 226 (90.8%) patients in the intramuscular group were compliant with their medications. Vaginal progesterone was associated with a lower percentage of deliveries before 34 weeks of gestation than the intramuscular preparation (p= 0.02). This association was also observed at 28 and 32 weeks of gestation (p= 0.04). Adverse effects were reported in 14.1% of patients in the intramuscular group, but in only 7.5% of patients in the vaginal group (p= 0.017).
CONCLUSIONS: Vaginal progesterone was more effective than intramuscular progesterone for the prevention of preterm birth and had fewer adverse effects.

© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.
PMID 23016508
G Saccone, A Khalifeh, A Elimian, E Bahrami, K Chaman-Ara, M A Bahrami, V Berghella
Vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials.
Ultrasound Obstet Gynecol. 2017 Mar;49(3):315-321. doi: 10.1002/uog.17245. Epub 2017 Feb 6.
Abstract/Text OBJECTIVE: Randomized controlled trials (RCTs) have recently compared intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB.
METHODS: Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17-OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB < 34 weeks. Secondary outcomes were SPTB < 37 weeks, < 32 weeks, < 28 weeks and < 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed.
RESULTS: Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17-OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB < 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53-0.95); low quality of evidence) and < 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40-0.94); low quality of evidence) compared with women who received 17-OHPC. There were no significant differences in the rates of SPTB < 37 weeks, < 28 weeks and < 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17-OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31-0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17-OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47-0.83); low quality of evidence). For the comparison of 17-OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions).
CONCLUSIONS: Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. COMPARACIÓN ENTRE LA PROGESTERONA VAGINAL Y EL 17Α-HIDROXIPROGESTERONA CAPROATO INTRAMUSCULAR PARA LA PREVENCIÓN DEL PARTO PRETÉRMINO ESPONTÁNEO RECURRENTE EN EMBARAZOS CON FETO ÚNICO: REVISIÓN SISTEMÁTICA Y METAANÁLISIS DE ENSAYOS CONTROLADOS ALEATORIOS: RESUMEN OBJETIVO: Recientemente se han realizado varios ensayos controlados aleatorios (ECA) que comparaban el caproato de 17α-hidroxiprogesterona (17-OHPC, por sus siglas en inglés) por vía intramuscular con la progesterona por vía vaginal para la reducción del riesgo de parto pretérmino espontáneo (PPTE) en embarazos con feto único de gestantes con historial de PPTE. El objetivo de esta revisión sistemática y metaanálisis fue evaluar la eficacia de la progesterona vaginal en comparación con la 17-OHPC en la prevención de embarazos con feto único de gestantes con historial de PPTE. MÉTODOS: Se realizaron búsquedas en bases de datos electrónicas para identificar todos los ECA con embarazos de feto único asintomáticos con historial de PPTE antes de ser asignados al azar a un tratamiento profiláctico, ya fuera con progesterona vaginal (grupo de intervención) o con 17-OHPC intramuscular (grupo de control). No se aplicaron restricciones respecto al idioma o la ubicación geográfica. El resultado primario fue PPTE < 34 semanas. Los resultados secundarios fueron PPTE <37 semanas, < 32 semanas, < 28 semanas y < 24 semanas, la reacción materna adversa al fármaco y los resultados neonatales. Las medidas del resumen se reportaron como riesgo relativo (RR) con IC del 95%. Para cada estudio incluido se evaluó el riesgo de sesgo.
RESULTADOS: Se incluyeron tres ECA (680 mujeres). La media de la edad gestacional en el momento de la aleatorización fue de 16 semanas. A las mujeres se les administró progesterona hasta la semana 36 o hasta el parto. Con respecto a la progesterona vaginal, un estudio utilizó gel de 90 mg diariamente, otro utilizó un supositorio diario de 100 mg y el otro utilizó un supositorio diario de 200 mg. Todos los ECA incluidos en el grupo de comparación utilizaron 250 mg semanales de 17-OHPC por vía intramuscular. Las mujeres que recibieron progesterona vaginal tuvieron tasas significativamente más bajas de PPTE < 34 semanas (17,5% vs. 25,0%; RR 0,71 (IC 95%, 0,53-0,95); calidad de la evidencia baja) y < 32 semanas (8,9% vs. 14,5%; RR 0,62 (IC 95%, 0,40-0,94); calidad de evidencia baja), en comparación con las mujeres que recibieron 17-OHPC. No hubo diferencias significativas en las tasas de PPTE < 37 semanas, < 28 semanas y < 24 semanas. La tasa de mujeres que reportaron reacciones adversas a los medicamentos fue significativamente menor en el grupo de progesterona vaginal en comparación con el grupo de 17-OHPC (7,1% vs. 13,2%; RR 0,53 (IC 95%, 0,31-0,91); calidad de la evidencia muy baja). En cuanto a los resultados neonatales, la progesterona vaginal se asoció a una menor tasa de admisiones en la unidad neonatal de cuidados intensivos en comparación con la 17-OHPC (18,7% vs. 23,5%; RR 0,63 (IC 95%, 0,47-0,83); calidad de evidencia baja). Para la comparación del 17-OHPC con la progesterona vaginal se rebajó la calidad de las pruebas para todos los resultados en al menos un grado debido a imprecisiones (no se alcanzó el tamaño óptimo de la información) y en al menos un grado debido al carácter indirecto de los estudios (diferentes intervenciones).
CONCLUSIONES: La progesterona vaginal administrada diariamente (ya fuera como supositorio o como gel) desde la semana 16 de gestación es una alternativa razonable, si no mejor, a una inyección semanal de 17-OHPC para la prevención de PPTE en mujeres con embarazos de feto único e historial de PPTE. Sin embargo, el nivel de calidad de las estimaciones del resumen fue bajo o muy bajo según lo evaluado por GRADE, lo que indica que el verdadero efecto puede ser, o es probable que sea, sustancialmente diferente de la estimación del efecto. 17Α-:META: : (randomized controlled trials,RCTs)(spontaneous preterm birth,SPTB)17α-(intramuscular 17α-hydroxyprogesterone caproate,17-OHPC)SPTB。metaSPTB17-OHPCSPTB。 : ,SPTBRCTs,RCTs()17-OHPC()。。34SPTB。37、32、2824SPTB,。(relative risk,RR)95%CI。。 : 3RCTs(680)。16。,36。,90 mg,100 mg,200 mg。,RCTs250 mg 17-OHPC。17-OHPC,34 [17.5%25.0%;RR,0.71(95% CI,0.53 ~ 0.95);]32[8.9%14.5%;RR,0.62(95% CI,0.40 ~ 0.94);]SPTB。37、2824SPTB。17-OHPC,[7.1%13.2%;RR,0.53(95% CI,0.31 ~ 0.91);]。,17-OHPC,[18.7%23.5%;RR,0.63(95% CI,0.47 ~ 0.83);]。17-OHPC,(),()。 : SPTBSPTB,16()17-OHPC,。,GRADE,,。.

Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
PMID 27546354
Jane E Norman, Fiona Mackenzie, Philip Owen, Helen Mactier, Kevin Hanretty, Sarah Cooper, Andrew Calder, Gary Mires, Peter Danielian, Stephen Sturgiss, Graeme MacLennan, Graham Tydeman, Steven Thornton, Bill Martin, James G Thornton, James P Neilson, John Norrie
Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.
Lancet. 2009 Jun 13;373(9680):2034-40. doi: 10.1016/S0140-6736(09)60947-8.
Abstract/Text BACKGROUND: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy.
METHODS: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581.
FINDINGS: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51).
INTERPRETATION: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy.
FUNDING: Chief Scientist Office of the Scottish Government Health Directorate.

PMID 19523680
E Schuit, S Stock, L Rode, D J Rouse, A C Lim, J E Norman, A H Nassar, V Serra, C A Combs, C Vayssiere, M M Aboulghar, S Wood, E Çetingöz, C M Briery, E B Fonseca, K Worda, A Tabor, E A Thom, S N Caritis, J Awwad, I M Usta, A Perales, J Meseguer, K Maurel, T Garite, M A Aboulghar, Y M Amin, S Ross, C Cam, A Karateke, J C Morrison, E F Magann, K H Nicolaides, N P A Zuithoff, R H H Groenwold, K G M Moons, A Kwee, B W J Mol, Global Obstetrics Network (GONet) collaboration
Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.
BJOG. 2015 Jan;122(1):27-37. doi: 10.1111/1471-0528.13032. Epub 2014 Aug 22.
Abstract/Text BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB).
OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA).
SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles.
SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment.
DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB.
MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75).
AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

© 2014 Royal College of Obstetricians and Gynaecologists.
PMID 25145491
J H Harger
Comparison of success and morbidity in cervical cerclage procedures.
Obstet Gynecol. 1980 Nov;56(5):543-8.
Abstract/Text A review of 251 cervical cerclage procedures in 205 women over a 7.5-year period was conducted to compare the success rate and morbidity of the Shirodkar and McDonald techniques. Fetal survival rate was 19% before 139 elective McDonald operations and 20% before 63 elective Shirodkar procedures. Fetal survival was 78% after elective McDonald operations and 87% after elective Shirodkar procedures, a difference that is not statistically significant (P > .05). Fetal survival rate was 53% after 30 emergency McDonald and 68% after 19 emergency Shirodkar procedures, a difference not statistically significant. Major postoperative morbidity occurred in 2.0% of the elective cerclage procedures, and acute chorioamnionitis accounted for half the complications (1.2%). Mean blood loss was 30 ml with McDonald operations and 44 ml with Shirodkar procedures; the maximum blood loss of 150 ml occurred in 2 emergency operations. Cervical laceration at parturition occurred more often with Shirodkar (11%) or McDonald (14%) procedures than with the 55,688 other deliveries (2.18%) during the 7.5-year study period (P < .001). Cervical scarring and elective cesarean section significantly (P < .025) increased the cesarean section rate to 16% after McDonald procedures and 25% after Shirodkar procedures.

PMID 7001296
E Caspi, D F Schneider, Z Mor, R Langer, Z Weinraub, I Bukovsky
Cervical internal os cerclage: description of a new technique and comparison with Shirodkar operation.
Am J Perinatol. 1990 Oct;7(4):347-9. doi: 10.1055/s-2007-999520.
Abstract/Text Internal os cerclage for cervical incompetence was performed in 90 patients who had previous McDonald procedure failure (70 patients) or had unfavorable cervical anatomy (short or lacerated cervix) for primary McDonald type cerclage (20 patients). Two different techniques were used: the Shirodkar operation (n = 44) with Mersilene band, and a simpler new technique (n = 46). The new technique is characterized by anterior colpotomy for exposure of the internal os, and a 0.6 mm nylon suture encircling the cervix to be tied high in the posterior fornix. The pregnancy outcome for both groups was similar. Late abortions of 8.7 and 11% and premature deliveries of 13 and 18% occurred in the new technique and the Shirodkar groups, respectively. The removal of the suture was generally difficult in the Shirodkar group and in eight patients analgesia and sedation were required. In the new technique group, the removal was easier and in only one patient was sedation required (p less than 0.0001). Severe vaginal discharge was found in 52% of the Shirodkar patients and none in the other group. Apparently the monofilament nylon suture prevented this side effect. It seems that the new technique is simpler to perform, involves fewer side effects, the removal of the suture is easier, and it is as effective as the Shirodkar procedure.

PMID 2222626
Anthony O Odibo, Vincenzo Berghella, Meekai S To, Orion A Rust, Sietske M Althuisius, Kypros H Nicolaides
Shirodkar versus McDonald cerclage for the prevention of preterm birth in women with short cervical length.
Am J Perinatol. 2007 Jan;24(1):55-60. doi: 10.1055/s-2006-958165. Epub 2006 Dec 27.
Abstract/Text The efficacy of Shirodkar cerclage was compared with that of the McDonald procedure for the prevention of preterm birth (PTB) in women with a short cervix. Secondary analysis using data from all published randomized trials including women with a short cervical length (CL) was performed comparing the use of Shirodkar versus McDonald sutures. Analysis was limited to singletons with short CL on transvaginal ultrasound. The primary outcome measure was PTB < 33 weeks. Statistical analysis was performed using bivariate and multivariable techniques. From 607 women randomly assigned in the study, 277 met our inclusion criteria; 127 received Shirodkar and 150 women received McDonald sutures. The mean ( +/- standard deviation) gestational age at delivery was 35.0 +/- 5.3 versus 36.3 +/- 4.7 for the Shirodkar versus McDonald groups, respectively ( p< 0.02). PTB < 33 weeks was seen in 61 (22%) of 277 women; 26 (20%) of 127 in the Shirodkar and 35 (23%) of 150 in the McDonald groups, respectively (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.5 to 1.6). On adjusting for confounders using logistic regression modeling, no significant difference in PTB < 33 weeks was found between the two groups (OR, 0.55; 95% CI, 0.2 to 1.3). In women with short cervical length randomly assigned to receiving cerclage, no significant difference in prevention of PTB was observed using Shirodkar or McDonald's procedures.

PMID 17195146
Heather A Cockwell, Graeme N Smith
Cervical incompetence and the role of emergency cerclage.
J Obstet Gynaecol Can. 2005 Feb;27(2):123-9.
Abstract/Text OBJECTIVE: To evaluate the role of emergency cerclage for women who present with a dilated external cervical os and bulging or "hour-glassing" membranes. We examined overall experiences at Kingston General Hospital (KGH) from 2000 to 2004 and conducted a literature review for the period January 1, 1995, to December 31, 2004.
METHODS: A search for cerclages placed by operators in Kingston revealed 12 pregnancies in the period between 2000 and 2004. We reviewed the charts for these women and for their infants. We conducted a literature review, using the terms "cerclage," "cervical," "emergent or emergency cerclage," "rescue cerclage," and "incompetent cervix," using an OVID interface to access MEDLINE records. We excluded articles in which the diagnosis of cervical incompetence was made using ultrasound, because its predictive value has not been shown in randomized trials. The most recent review of this type was carried out in 1995; since then, an additional 24 articles have been published that met our inclusion and exclusion criteria.
RESULTS: The average time between cerclage placement and delivery at KGH was 7 weeks, which allowed for 10 of 13 infants (one twin pregnancy) to be born at 28 weeks or later. Three infants were born weighing under 1 kg; the 10 remaining infants weighed over 1 kg. Histological data are available for 12 placentas of the 13 infants delivered; 7 infants had a histological diagnosis of chorioamnionitis; none of the blood cultures from any of the infants post-delivery revealed septicemia. The literature review identified 638 women. Where reported, the average prolongation of the pregnancy was 7 weeks plus 1 day. This allowed for 60% of infants (range 26% to 80%) to be born after 28 weeks, with an average neonatal survival of over 70% (range 47.2% to 96%). Preterm premature rupture of membranes complicated an average of 29% of pregnancies (range 1% to 58%), and chorioamnionitis was reported in 5% to 80% of pregnancies.
CONCLUSIONS: The KGH data collected and the data available in the literature suggest that emergency cerclage, under ideal circumstances, can significantly prolong pregnancy and increase the chance of viable pregnancy outcome. However, in counselling women about the potential therapeutic benefit of emergency cerclage, the increased risk of chorioamnionitis and its associated risk of fetal inflammatory brain injury, as well as the risk of extending a pregnancy from pre-viability to severe prematurity, should be discussed. A longer-term follow-up than has been carried out here is required for better elucidation of the effect of chorioamnionitis on those infants in childhood and beyond.

PMID 15937588
M Kurup, J W Goldkrand
Cervical incompetence: elective, emergent, or urgent cerclage.
Am J Obstet Gynecol. 1999 Aug;181(2):240-6.
Abstract/Text OBJECTIVE: We define criteria for insertion of cervical cerclage done electively (historical), urgently (in patients without symptoms), or emergently (in patients with symptoms). We compare outcomes as determined by prolongation of pregnancy and survival in each of these groups, and we define whether urgent or emergent cerclage imparted a higher risk of spontaneous rupture of membranes or chorioamnionitis than that associated with elective cerclage.
STUDY DESIGN: This is a retrospective analysis of all cervical cerclages placed at Memorial Medical Center between January 1, 1993, and December 31, 1997. Outcomes oberved were as follows: (1) prolongation of pregnancy in weeks after cervical cerclage, (2) presence of spontaneous rupture of membranes or clinical chorioamnionitis necessitating delivery, and (3) neonatal outcome.
RESULTS: For prolongation of pregnancy the following results were obtained: emergent cerclage, 8.3 +/- 0.9 weeks; urgent cerclage, 12.2 +/- 1.5 weeks; and elective cerclage, 20.2 +/- 0.9 weeks (elective versus emergent and urgent, P <.05). For average gestational age at delivery, the results were as follows: emergent cerclage, 30.5 +/- 0.9 weeks; urgent cerclage, 33.1 +/- 1.4 weeks; and elective cerclage, 35.5 +/- 0.9 weeks (elective versus emergent and urgent, P <.05). The total neonatal survival was 85.7%. The incidence of spontaneous rupture of membranes was as follows: emergent cerclage, 51%; urgent cerclage, 40%; elective cerclage, 18% (elective versus emergent and urgent, P <.05). The incidence of clinical chorioamnionitis showed similar results.
CONCLUSIONS: It is clear that emergency cerclages confer some benefit in patients with evidence of cervical incompetence. From this study it is evident that there is a new group of patients who need cerclage on an urgent basis as shown by subtle ultrasonographic changes in the cervix. Their behavior mirrors that of those belonging to the emergent group, suggesting that if they were left untreated they would need cerclage on an emergency basis.

PMID 10454663
S S Hassan, R Romero, E Maymon, S M Berry, S C Blackwell, M C Treadwell, M Tomlinson
Does cervical cerclage prevent preterm delivery in patients with a short cervix?
Am J Obstet Gynecol. 2001 Jun;184(7):1325-9; discussion 1329-31.
Abstract/Text OBJECTIVE: Our purpose was to determine whether cerclage placement in women with a short cervix on transvaginal ultrasonography reduces the rate of preterm delivery.
STUDY DESIGN: A retrospective cohort study identified patients with an ultrasonographic short cervix (cervical length < or =15 mm) between 14 and 24 weeks' gestation. Cerclage placement was performed at the discretion of the attending physician. Clinical characteristics and outcome with and without cerclage were compared.
RESULTS: Seventy patients met inclusion criteria; 25 (36%) underwent cerclage placement. Patients managed with cerclage had a lower gestational age at diagnosis (19.6 weeks vs 21.3 weeks, P <.01) but had a similar median cervical length, presence of funneling, and a history of cervical surgery, in comparison with those managed without cerclage. The rate of spontaneous preterm delivery was not different between groups. Patients with cerclage had a higher rate of preterm premature rupture of membranes than those without cerclage (65.2% vs 36.4%, P <.05).
CONCLUSION: Cervical cerclage in patients with a short cervix did not reduce the rate of spontaneous preterm delivery and increased the risk of preterm premature rupture of membranes.

PMID 11408848
Jenny Wu, Anna E Denoble, Jeffrey A Kuller, Sarah K Dotters-Katz
Management of Cerclage in Patients With Preterm Prelabor Rupture of Membranes.
Obstet Gynecol Surv. 2021 Nov;76(11):681-691. doi: 10.1097/OGX.0000000000000957.
Abstract/Text Importance: Women undergoing cerclage placement remain at high risk for preterm labor and preterm prelabor rupture of membranes (PPROMs). The management of cervical cerclage after PPROM is controversial given the potential for prolonged latency when the cerclage is kept in place balanced with a potential increased risk of maternal infectious morbidity.
Objective: In this review, we compared studies that examined maternal, fetal, and neonatal outcomes in women with cerclage at the time of PPROM. We evaluated latency after PPROM and maternal and neonatal complications in the setting of PPROM with cervical cerclage.
Evidence Acquisition: Original research articles, review articles, and guidelines on cerclage removal were reviewed.
Results: Nine studies comparing cerclage retention versus removal were examined with mixed results, in particular between studies before the routine use of latency antibiotics and corticosteroid administration. There was an associated increase in latency to delivery with retention of cerclage, with a potential increase in maternal infectious morbidity. No significant differences were noted for neonatal mortality, neonatal sepsis, or other neonatal morbidity outcomes. The majority of studies were limited by their retrospective nature and small sample sizes.
Conclusions and Relevance: Cerclage removal at the time of diagnosis of PPROM can be considered due to the concern for increased risk of maternal morbidity without definitive benefit in latency to delivery or neonatal outcomes. However, data are limited, and clinicians should engage in shared decision-making with patients in this setting.

PMID 34854925

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