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Cervical dilation before first-trimester surgical abortion (<14 weeks' gestation)

      Abstract

      First-trimester surgical abortion is a common, safe procedure with a major complication rate of less than 1%. Cervical dilation before suction abortion is usually accomplished using tapered mechanical dilators. Risk factors for major complications in the first trimester include increasing gestational age and provider inexperience. Cervical priming before first-trimester surgical abortion has been studied using osmotic dilators and pharmacologic agents, most commonly misoprostol. Extensive data demonstrate that a variety of agents are safe and effective at causing preoperative cervical softening and dilation; however, given the small absolute risk of complications, the benefit of routine use of misoprostol or osmotic dilators in first-trimester surgical abortion is unclear. Although cervical priming results in reduced abortion time and improved provider ease, it requires a delay of at least 1 to 3 h and may confer side effects. The Society of Family Planning does not recommend routine cervical priming for first-trimester suction abortion but recommends limiting consideration of cervical priming for women at increased risk of complications from cervical dilation, including those late in the first trimester, adolescents and women in whom cervical dilation is expected to be challenging.

      Keywords

      1. Background

      Induced abortion is one of the most common surgical procedures in the United States. In 2011, 1.06 million pregnancies were terminated, approximately 88% of them at less than 14 weeks of gestation [
      • Jones R.K.
      • Jerman J.
      Abortion incidence and service availability in the United States, 2011.
      ]. First-trimester surgical abortion is safe, with a mortality rate of 0.7 per 100,000 procedures performed at less than 13 weeks of gestation and a major complication rate of less than 1% [
      • Bartlett L.A.
      • Berg C.J.
      • Shulman H.B.
      • Zane S.B.
      • Green C.A.
      • Whitehead S.
      • et al.
      Risk factors for legal induced abortion-related mortality in the United States.
      ,
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ,
      • Pazol K.
      • Creanga A.A.
      • Burley K.D.
      • Jamieson D.J.
      Abortion surveillance - United States, 2011.
      ,
      • Raymond E.G.
      • Grimes D.A.
      The comparative safety of legal induced abortion and childbirth in the United States.
      ]. The rate of recognized uterine perforation during first-trimester surgical abortion ranges from 0.1 to 4.0 per 1000 procedures [
      • Royal College of General Practitioners
      • Royal College of Obstetricians and Gynaecologists
      Induced abortion operations and their early sequelae.
      ,
      • Andolsek L.
      • Cheng M.
      • Hren M.
      • Ogrinc-Oven M.
      • Ng A.
      • Ratnam S.
      • et al.
      The safety of local anesthesia and outpatient treatment: a controlled study of induced abortion by vacuum aspiration.
      ,
      • Nesheim B.I.
      Induced abortion by the suction method. An analysis of complication rates.
      ,
      • Cates Jr., W.
      • Schulz K.F.
      • Grimes D.A.
      The risks associated with teenage abortion.
      ,
      • Heisterberg L.
      • Kringelbach M.
      Early complications after induced first-trimester abortion.
      ,
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ,
      • Ferris L.E.
      • McMain-Klein M.
      • Colodny N.
      • Fellows G.F.
      • Lamont J.
      Factors associated with immediate abortion complications.
      ,
      • Zhou W.
      • Nielsen G.L.
      • Moller M.
      • Olsen J.
      Short-term complications after surgically induced abortions: a register-based study of 56 117 abortions.
      ,
      • Grimes D.A.
      • Schulz K.F.
      • Cates Jr., W.J.
      Prevention of uterine perforation during curettage abortion.
      ,
      • Bozorgi N.
      Statistical analysis of first-trimester pregnancy terminations in an ambulatory surgical center.
      ,
      • Hodgson J.E.
      • Portmann K.C.
      Complications of 10,453 consecutive first-trimester abortions: a prospective study.
      ,
      • Lindell G.
      • Flam F.
      Management of uterine perforations in connection with legal abortions.
      ,
      • King T.M.
      • Atienza M.F.
      • Burkman R.T.
      The incidence of abdominal surgical procedures in a population undergoing abortion.
      ,
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ]. The rate of all types of cervical injury ranges from 0.1 to 10.0 per 1000 procedures, with higher rates in adolescents (age ≤17) [
      • Royal College of General Practitioners
      • Royal College of Obstetricians and Gynaecologists
      Induced abortion operations and their early sequelae.
      ,
      • Andolsek L.
      • Cheng M.
      • Hren M.
      • Ogrinc-Oven M.
      • Ng A.
      • Ratnam S.
      • et al.
      The safety of local anesthesia and outpatient treatment: a controlled study of induced abortion by vacuum aspiration.
      ,
      • Nesheim B.I.
      Induced abortion by the suction method. An analysis of complication rates.
      ,
      • Cates Jr., W.
      • Schulz K.F.
      • Grimes D.A.
      The risks associated with teenage abortion.
      ,
      • Heisterberg L.
      • Kringelbach M.
      Early complications after induced first-trimester abortion.
      ,
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ,
      • Ferris L.E.
      • McMain-Klein M.
      • Colodny N.
      • Fellows G.F.
      • Lamont J.
      Factors associated with immediate abortion complications.
      ,
      • Zhou W.
      • Nielsen G.L.
      • Moller M.
      • Olsen J.
      Short-term complications after surgically induced abortions: a register-based study of 56 117 abortions.
      ,
      • Bozorgi N.
      Statistical analysis of first-trimester pregnancy terminations in an ambulatory surgical center.
      ,
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ,
      • Jacot F.R.
      • Poulin C.
      • Bilodeau A.P.
      • Morin M.
      • Moreau S.
      • Gendron F.
      • et al.
      A five-year experience with second-trimester induced abortions: no increase in complication rate as compared to the first trimester.
      ]. The rate of immediate complications depends on provider experience and gestational age. Within the complication ranges reported above, the higher complication rates come from studies with a large proportion of trainee physicians. Lower complication rates are associated with experienced providers in high-volume outpatient clinics [
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ]. Accumulated evidence also shows comparable safety when first-trimester abortions are performed by advanced practice clinicians or physicians [
      • Weitz T.A.
      • Taylor D.
      • Desai S.
      • Upadhyay U.D.
      • Waldman J.
      • Battistelli M.F.
      • et al.
      Safety of aspiration abortion performed by nurse practitioners, certified nurse midwives, and physician assistants under a California legal waiver.
      ].
      Shortly after the legalization of induced abortion in the United States, studies demonstrated that the use of laminaria, an osmotic dilator, was associated with a reduced risk of cervical laceration and, to a lesser extent, uterine perforation [
      • Grimes D.A.
      • Schulz K.F.
      • Cates Jr., W.J.
      Prevention of uterine perforation during curettage abortion.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ,
      • Hale R.W.
      • Pion R.J.
      Laminaria: an underutilized clinical adjunct.
      ]. These reduced risks were observed primarily in settings with a high baseline complication rate. Reports also demonstrated the usefulness of laminaria in reducing pain associated with rigid dilation, allowing the use of local anesthesia alone, although these studies lacked a control group [
      • Golditch I.M.
      • Glasser M.H.
      The use of laminaria tents for cervical dilatation prior to vacuum aspiration abortion.
      ,
      • Niswander K.R.
      Laminaria tents as an aid in suction abortion.
      ,
      • Hern W.M.
      Laminaria in abortion. Use in 1368 patients in first trimester.
      ]. Other studies hypothesized that passive dilation of the cervix with prostaglandins or similar agents might avert uterine perforation and cervical laceration through a reduction in the force required for dilation [
      • Moberg P.
      Uterine perforation in connection with vacuum aspiration.
      ,
      • Borell U.
      • Bygdeman M.
      • Leader A.
      • Lundstrom V.
      • Martin Jr., J.N.
      Successful first trimester abortion with 15(S) 15-methyl-prostaglandin F2alpha-methyl ester vaginal suppositories.
      ]. In addition, older medical literature reflects a concern that forceful cervical dilation may cause permanent damage to the cervical tissue, leading to poor reproductive outcomes [
      • Golditch I.M.
      • Glasser M.H.
      The use of laminaria tents for cervical dilatation prior to vacuum aspiration abortion.
      ,
      • Gupta J.K.
      • Johnson N.
      Should we use prostaglandins, tents or progesterone antagonists for cervical ripening before first trimester abortion?.
      ,
      • Nicolaides K.H.
      • Welch C.C.
      • MacPherson M.B.
      • Johnson I.R.
      • Filshie G.M.
      Lamicel: a new technique for cervical dilatation before first trimester abortion.
      ,
      • Morris N.D.
      • McCallum G.I.
      • Hammond L.
      Preoperative cervical dilatation: a trial of laminaria tents and prostaglandin F2 alpha gel.
      ,
      • Sema S.
      • Hingorani V.
      • Kumar S.
      • Kinra G.
      Three methods for gradual cervical dilatation prior to vacuum aspiration in late first trimester pregnancy.
      ,
      • Hulka J.F.
      • Lefler Jr., H.T.
      • Anglone A.
      • Lachenbruch P.A.
      A new electronic force monitor to measure factors influencing cervical dilation for vacuum curettage.
      ,
      • Wheeler R.G.
      • Schneider K.
      Properties and safety of cervical dilators.
      ]. Cervical priming was therefore recommended to prevent such long-term complications as spontaneous abortion, cervical insufficiency and preterm delivery. However, subsequent large population-based prospective studies have shown no association between induced abortion and subsequent adverse pregnancy outcomes [
      • Zhou W.
      • Olsen J.
      Are complications after an induced abortion associated with reproductive failures in a subsequent pregnancy?.
      ,
      • Zhou W.
      • Olsen J.
      • Nielsen G.L.
      • Sabroe S.
      Risk of spontaneous abortion following induced abortion is only increased with short interpregnancy interval.
      ,
      • Zhou W.
      • Sorensen H.T.
      • Olsen J.
      Induced abortion and low birthweight in the following pregnancy.
      ,
      • Hogue C.J.
      • Boardman L.A.
      • Stotland N.
      Answering questions about long-term outcomes.
      ,
      • Raatikainen K.
      • Heiskanen N.
      • Heinonen S.
      Induced abortion: not an independent risk factor for pregnancy outcome, but a challenge for health counseling.
      ]. Cervical priming prior to first-trimester abortion fell out of favor until the emergence of misoprostol, an agent easier to administer than osmotic dilators.
      This guideline:
      • 1.
        Discusses the methods of cervical dilation before first-trimester surgical abortion.
      • 2.
        Discusses risk factors for immediate complications from cervical dilation.
      • 3.
        Explores the evidence for and against the use of cervical priming agents in the first trimester based on safety, efficacy and acceptability.
      • 4.
        Discusses mechanical dilation, osmotic dilators, prostaglandin analogues and progesterone antagonists.

      1.1 Rigid dilation

      When cervical dilation is needed, most North American providers employ rigid dilation alone with steel Pratt dilators (Fig. 1a ) or the plastic equivalent, Denniston dilators [
      • Meckstroth K.
      • Paul M.
      First-trimester aspiration abortion.
      ]. The Pratt dilator is characterized by a gradual taper at the end of the instrument and comes in sizes ranging from 9 to 79 F. For most pregnant women, dilation can be initiated easily with a 17-F dilator. Each French unit refers to the circumference of the dilator in millimeters. To obtain the diameter of the dilator in millimeters, the French unit is divided by Pi (approximately 3). By comparison, Hegar dilators (Fig. 1b) have a blunt end and come in sizes ranging from 1 to 26 mm in diameter. Hegar dilators increase in size more rapidly than tapered dilators, potentially reducing the time necessary for dilation but also requiring more force [
      • Hulka J.F.
      • Lefler Jr., H.T.
      • Anglone A.
      • Lachenbruch P.A.
      A new electronic force monitor to measure factors influencing cervical dilation for vacuum curettage.
      ,
      • Novak F.
      • Andolsek L.
      Comparison of the medical effects of induced abortion by two methods, curettage and vacuum aspiration.
      ]. It is easier to sense the loss of resistance of the internal os with Hegar dilators than with Pratt dilators [
      • Meckstroth K.
      • Paul M.
      First-trimester aspiration abortion.
      ]. No trials have compared the safety and efficacy of Pratt and Hegar dilators. A minority of providers report using the Hegar dilator [
      • Lichtenberg E.S.
      • Paul M.
      • Jones H.
      First trimester surgical abortion practices: a survey of National Abortion Federation members.
      ].
      Figure thumbnail gr1
      Fig. 1Reproduced with permission from: Stovall DW. Dilation and curettage. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on 8/11/2015.) Copyright © 2015 UpToDate, Inc. For more information visit www.uptodate.com.

      1.2 Cervical priming agents

      Cervical priming can be accomplished mechanically with osmotic dilators that absorb moisture from the cervix and slowly expand to dilate the cervical os or biochemically with prostaglandin analogues or progesterone antagonists. The commercially available options for cervical priming include osmotic dilators, laminaria and Dilapan-S, as well as pharmacological agents such as misoprostol (PGE1), gemeprost (PGE1), dinoprostone (PGE2) and mifepristone. Other agents for cervical priming include nitric oxide donors (e.g., isosorbide mononitrate, glyceryl trinitrate?), which are currently under study. As of 2002, 18% of North American providers routinely used misoprostol for cervical ripening prior to 11 weeks' gestation, and 16% used it for multiparous women. Beginning at 11 to 12 weeks of gestation, 25% used misoprostol for nulliparous women and 20% for multiparous women [
      • O'Connell K.
      • Jones H.E.
      • Simon M.
      • Saporta V.
      • Paul M.
      • Lichtenberg E.S.
      First-trimester surgical abortion practices: a survey of National Abortion Federation members.
      ].

      1.3 Osmotic dilators

      Two types of osmotic dilators are available in the United States: laminaria tents made of seaweed and synthetic dilators. All osmotic dilators require a trained provider and a speculum examination for insertion.
      Laminaria tents are dried compressed stalks of hygroscopic seaweed (Laminaria digitata, Laminaria japonicum) that absorb water from the cervical stroma, swelling to three or four times their dry diameter overnight. Laminaria tents are available in multiple dry diameters. Laminaria apply radial force to the walls of the cervical canal and also induce the local production of prostaglandins to promote dilation [
      • Olund A.
      • Jonasson A.
      • Kindahl H.
      • Fianu S.
      • Larsson B.
      The effect of cervical dilatation by laminaria on the plasma levels of 15-keto-13,14-dihydro-PGF2 alpha.
      ,
      • Jonasson A.
      • Larsson B.
      Contractile activity in the human uterine cervix and corpus during cervical dilatation by laminaria tent in first trimester legal abortions.
      ].
      Laminaria are safe; adverse events following their use occur infrequently. Since bacterial spores can remain despite treatment of the laminaria with ethylene oxide or irradiation for sterilization, clinicians have worried about the risk of infection with laminaria. Case reports have described bacteremia following laminaria placement in the second trimester [
      • Sutkin G.
      • Capelle S.D.
      • Schlievert P.M.
      • Creinin M.D.
      Toxic shock syndrome after laminaria insertion.
      ,
      • Acharya P.S.
      • Gluckman S.J.
      Bacteremia following placement of intracervical laminaria tents.
      ]. Researchers theorize that laminaria insertion can facilitate the transfer of cervical or vaginal flora into the uterine cavity and cause an ascending infection [
      • Evaldson G.R.
      • Fianu S.
      • Jonasson A.
      • Larsson B.
      • Nord C.E.
      • Olund A.R.
      Does the hygroscopic property of the laminaria tent imply a risk for ascending infection in legal abortions? A microbiological study.
      ]. However, a randomized trial comparing laminaria and rigid dilation in first-trimester abortion found no significant difference in rates of postabortion infection [
      • Jonasson A.
      • Larsson B.
      • Bygdeman S.
      • Forsum U.
      The influence of cervical dilatation by laminaria tent and with Hegar dilators on the intrauterine microflora and the rate of postabortal pelvic inflammatory disease.
      ]. In the first trimester, all osmotic devices are generally removed no later than 24 h after insertion to reduce the possibility of infection. Because laminarias derive from a natural material, their use rarely results in hypersensitivity reactions (urticaria, angioedema, respiratory distress) and anaphylaxis in women with previous exposure [
      • Kim S.H.
      • Chang Y.H.
      • Kim W.K.
      • Kim Y.K.
      • Cho S.H.
      • Kim Y.Y.
      • et al.
      Two cases of anaphylaxis after laminaria insertion.
      ,
      • Chanda M.
      • Mackenzie P.
      • Day J.H.
      Hypersensitivity reactions following laminaria placement.
      ,
      • Nguyen M.T.
      • Hoffman D.R.
      Anaphylaxis to laminaria.
      ]. The true incidence of this reaction is unknown. Investigators believe that the mechanism for this allergic reaction is IgE-mediated [
      • Chanda M.
      • Mackenzie P.
      • Day J.H.
      Hypersensitivity reactions following laminaria placement.
      ].
      Use of laminaria before first-trimester surgical abortion may pose an access barrier: laminaria acts slowly and often require an extra visit. To address the limitations of laminaria, investigators created two synthetic dilators, Dilapan-S (GelMed International, Czech Republic) and Lamicel® (Medtronic, Mystic, CT, USA), which are sterile and swell more rapidly than laminaria. An additional advantage of synthetic dilators is the consistency of length and shape, which leads to more predictable results.
      Dilapan-S is a rod-shaped hydrophilic dilator made from polyacrylate-based hydrogel (Hypan) available in the following dimensions: 3 mm×55 mm, 4 mm×55 mm and 4 mm×65 mm. Dilapan-S absorbs moisture from the cervical tissue; in 4 h, the 3-mm diameter swells to an average of 8 to 9 mm, and the 4-mm diameter swells to an average of 10 to 11 mm, according to the manufacturer. In the United States, the Dilapan-S product label recommends one device placed up to 4 h prior to suction abortion in gestations of less than 16 weeks. In other countries, Dilapan-S is not subject to limitations on number of devices, indication or duration of use. Therefore, US providers commonly use Dilapan-S in an off-label fashion. Problems from breakage due to entrapment with the original version of Dilapan were resolved with release of a new formulation in 1998 internationally and in 2002 in the United States [
      • Usta I.M.
      • Khalil A.
      Long-term complications and ultrasound findings in retained Dilapan fragments.
      ]. The reformulated Dilapan, named Dilapan-S, has not generated any reports of breakage [
      • Canvin J.
      Personal communication.
      ]. Advantages of Dilapan-S are its significant radial force and rapid swelling, making it ideal for same-day procedures.
      Lamicel, a polyvinyl alcohol polymer sponge impregnated with 450-mg magnesium sulfate and compressed to form a thin cylindrical tent, is no longer available in the United States. When placed in the cervical canal, Lamicel absorbs water from the cervical stroma and swells to four times its original size, transforming itself into a soft sponge [
      • Nicolaides K.H.
      • Welch C.C.
      • MacPherson M.B.
      • Johnson I.R.
      • Filshie G.M.
      Lamicel: a new technique for cervical dilatation before first trimester abortion.
      ,
      • Nicolaides K.H.
      • Welch C.C.
      • Koullapis E.N.
      • Filshie G.M.
      Cervical dilatation by Lamicel--studies on the mechanism of action.
      ]. Lamicel's mechanism of action is biochemical rather than mechanical, exerting no outward pressure on the cervical canal [
      • Wheeler R.G.
      • Schneider K.
      Properties and safety of cervical dilators.
      ]. Lamicel reduces the amount of force needed to dilate the cervix [
      • Nicolaides K.H.
      • Welch C.C.
      • MacPherson M.B.
      • Johnson I.R.
      • Filshie G.M.
      Lamicel: a new technique for cervical dilatation before first trimester abortion.
      ,
      • Wheeler R.G.
      • Schneider K.
      Properties and safety of cervical dilators.
      ] and is approved by the Food and Drug Administration for cervical priming for gestations of less than 16 weeks. Lamicel is significantly easier to remove than laminaria or Dilapan-S. Although Lamicel is the most expensive osmotic dilator, it often takes multiple laminaria to achieve the same priming effect that one Lamicel can produce in 4 h. Lamicel is 75-mm long and is available in either 3-mm or 5-mm dry diameters internationally.

      1.4 Pharmacologic agents

      Pharmacologic agents, such as prostaglandin analogues and progesterone antagonists, can be used for cervical priming in the first trimester. Misoprostol is the medication most commonly used for cervical priming [
      • Meckstroth K.R.
      • Darney P.D.
      Prostaglandins for first-trimester termination.
      ]. Misoprostol is a PGE1 synthetic analogue marketed as an oral preparation to prevent and treat gastroduodenal damage induced by nonsteroidal antiinflammatory drugs (NSAIDs). E-series prostaglandins are preferred over F-series prostaglandins because they stimulate uterine smooth muscle more than intestinal or vascular smooth muscle and do not cause bronchoconstriction [
      • O'Brien W.F.
      The role of prostaglandins in labor and delivery.
      ]. Misoprostol's advantages are its low cost, long shelf life and lack of need for refrigeration. Other prostaglandins, such as gemeprost and dinoprostone, are not used for cervical priming before surgical dilation in North America because they are more expensive but no better than misoprostol at cervical priming [
      • Eckerhovd E.
      • Radulovic N.
      • Norstrom A.
      Gemeprost versus misoprostol for cervical priming before first-trimester abortion: a randomized controlled trial.
      ,
      • Henry A.M.
      • Haukkamaa M.
      Comparison of vaginal misoprostol and gemeprost as pre-treatment in first trimester pregnancy interruption.
      ,
      • Platz-Christensen J.J.
      • Nielsen S.
      • Hamberger L.
      Is misoprostol the drug of choice for induced cervical ripening in early pregnancy termination?.
      ,
      • el-Refaey H.
      • Calder L.
      • Wheatley D.N.
      • Templeton A.
      Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost.
      ]; in addition, they require refrigeration for transport and storage [
      • Sparrow M.J.
      • Tait J.D.
      • Stone P.R.
      Vaginal dinoprostone versus oral misoprostol for predilatation of the cervix in first trimester surgical abortion.
      ].
      Investigators have examined different routes of misoprostol administration. The ideal route must take into account not only efficacy but also patient and staff acceptance and convenience. Misoprostol can be administered orally, vaginally, sublingually, buccally or rectally. Pharmacokinetics studies comparing oral and vaginal administration (Fig. 2) have shown that vaginal misoprostol is associated with slower absorption, lower peak plasma levels and slower clearance, similar to an oral extended-release preparation [
      • Zieman M.
      • Fong S.K.
      • Benowitz N.L.
      • Banskter D.
      • Darney P.D.
      Absorption kinetics of misoprostol with oral or vaginal administration.
      ,
      • Danielsson K.G.
      • Marions L.
      • Rodriguez A.
      • Spur B.W.
      • Wong P.Y.
      • Bygdeman M.
      Comparison between oral and vaginal administration of misoprostol on uterine contractility.
      ,
      • Khan R.U.
      • El-Refaey H.
      • Sharma S.
      • Sooranna D.
      • Stafford M.
      Oral, rectal, and vaginal pharmacokinetics of misoprostol.
      ]. Vaginal misoprostol is also associated with a greater overall exposure to the drug, area under the curve (AUC) and greater effects on the cervix and uterus [
      • Danielsson K.G.
      • Marions L.
      • Rodriguez A.
      • Spur B.W.
      • Wong P.Y.
      • Bygdeman M.
      Comparison between oral and vaginal administration of misoprostol on uterine contractility.
      ]. There is no clinically significant difference between vaginal misoprostol that is administered dry and vaginal misoprostol moistened with water, saline or acetic acid [
      • Tang O.S.
      • Schweer H.
      • Seyberth H.W.
      • Lee S.W.
      • Ho P.C.
      Pharmacokinetics of different routes of administration of misoprostol.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Does an acidic medium enhance the efficacy of vaginal misoprostol for pre-abortion cervical priming?.
      ,
      • Creinin M.D.
      • Carbonell J.L.
      • Schwartz J.L.
      • Varela L.
      • Tanda R.
      A randomized trial of the effect of moistening misoprostol before vaginal administration when used with methotrexate for abortion.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Chan Y.M.
      • Ho P.C.
      Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation: efficacy and acceptability.
      ]. The rectal route of administration shows a pattern similar to vaginal administration but a lower AUC, including a significantly lower maximum peak concentration [
      • Khan R.U.
      • El-Refaey H.
      • Sharma S.
      • Sooranna D.
      • Stafford M.
      Oral, rectal, and vaginal pharmacokinetics of misoprostol.
      ]. The sublingual route of administration has an AUC similar to vaginal administration but more rapid absorption and higher peak levels than either vaginal or oral administration [
      • Aronsson A.
      • Bygdeman M.
      • Gemzell-Danielsson K.
      Effects of misoprostol on uterine contractility following different routes of administration.
      ]. This translates into higher rates of gastrointestinal side effects. The sublingual route also causes uterine contractions at a rate equivalent to vaginal administration [
      • Aronsson A.
      • Bygdeman M.
      • Gemzell-Danielsson K.
      Effects of misoprostol on uterine contractility following different routes of administration.
      ]. The buccal route of administration shows a lower AUC, a lower peak concentration, and fewer side effects than sublingual administration [
      • Schaff E.A.
      • DiCenzo R.
      • Fielding S.L.
      Comparison of misoprostol plasma concentrations following buccal and sublingual administration.
      ]. The buccal route has a pattern of absorption similar to the vaginal route but produces lower serum levels overall. Nevertheless, the buccal route of administration produces uterine tone and activity similar to that resulting from vaginal administration. The buccal route of administration is also felt to be the least variable in terms of drug exposure and peak levels [
      • Meckstroth K.R.
      • Whitaker A.K.
      • Bertisch S.
      • Goldberg A.B.
      • Darney P.D.
      Misoprostol administered by epithelial routes: drug absorption and uterine response.
      ]. The administration of NSAIDs for pain relief does not alter the efficacy of misoprostol for cervical priming [
      • Li C.F.I.
      • Wong C.Y.G.
      • Chan C.P.B.
      • Ho P.C.
      A study of co-treatment of nonsteroidal anti-inflammatory drugs (NSAIDs) with misoprostol for cervical priming before suction termination of first trimester pregnancy.
      ].
      Figure thumbnail gr2
      Fig. 2Reprinted from Tang OS, Schweer H, Seyberth HW, Lee W, Ho PC. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17:332-6. Copyright © 2002 with permission from Oxford University Press.
      Mean plasma concentrations of misoprostol acid over time (arrow bars = 1 SD).
      The adverse effects caused by misoprostol have prompted research into other agents that can dilate the cervix effectively without causing abdominal pain, nausea, vomiting and diarrhea. Mifepristone is a progesterone antagonist that withdraws hormonal support of the pregnancy [
      • Bokstrom H.
      • Atterfelt P.
      • Alexandersson M.
      • Brannstrom M.
      • Norstrom A.
      Preoperative cervical softening before first trimester legal abortion by mifepristone and misoprostol: a double-blind, randomized, clinical, biochemical, and immunohistochemical study.
      ,
      • Johnson N.
      • Bryce F.C.
      Could antiprogesterones be used as alternative cervical ripening agents?.
      ,
      • Durlot F.
      • Dubois C.
      • Brunerie J.
      • Frydman R.
      Efficacy of progesterone antagonist RU486 (mifepristone) for pre-operative cervical dilatation during first trimester abortion.
      ,
      • Radestad A.
      • Christensen N.J.
      • Stromberg L.
      Induced cervical ripening with mifepristone in first trimester abortion. A double-blind randomized biomechanical study.
      ], causing cervical softening [
      • Swahn M.L.
      • Bygdeman M.
      The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin.
      ]. One randomized trial suggests that mifepristone is as effective at cervical priming as misoprostol and better tolerated [
      • Ashok P.W.
      • Flett G.M.
      • Templeton A.
      Mifepristone versus vaginally administered misoprostol for cervical priming before first-trimester termination of pregnancy: a randomized, controlled study.
      ]. Nevertheless, mifepristone, while effective at cervical priming, is not often utilized because of its high cost and limited availability in many clinical settings. In addition, mifepristone is typically administered 24 h prior to a procedure, where misoprostol is administered 2–3 h prior. Both misoprostol and mifepristone are believed to exert their effects on the cervix via nitric oxide [
      • Vaisanen-Tommiska M.
      • Butzow R.
      • Ylikorkala O.
      • Mikkola T.S.
      Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy.
      ,
      • Vaisanen-Tommiska M.
      • Mikkola T.S.
      • Ylikorkala O.
      Misoprostol induces cervical nitric oxide release in pregnant, but not in nonpregnant, women.
      ]. Because nitric oxide inhibits contractions in the uterus but still induces cervical softening, nitric oxide donors have been investigated as potential cervical priming agents [
      • Chwalisz K.
      • Garfield R.E.
      Role of nitric oxide in the uterus and cervix: implications for the management of labor.
      ]. While nitric oxide donors (e.g., isosorbide mononitrate) are more effective than placebo or no treatment in dilating the cervix, a systematic review found that prostaglandins were superior to nitric oxide donors [
      • Promsonthi P.
      • Preechapornprasert D.
      • Chanrachakul B.
      Nitric oxide donors for cervical ripening in first-trimester surgical abortion.
      ]. Furthermore, nitric oxide donors were associated with their own side effect profile of headache, palpitations and dizziness.
      Most providers in North America continue to use rigid dilators for cervical dilation without preoperative priming [
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ,
      • Ferris L.E.
      • McMain-Klein M.
      • Colodny N.
      • Fellows G.F.
      • Lamont J.
      Factors associated with immediate abortion complications.
      ,
      • Lichtenberg E.S.
      • Paul M.
      • Jones H.
      First trimester surgical abortion practices: a survey of National Abortion Federation members.
      ]. They do so because the risk of uterine perforation or cervical laceration with first-trimester suction aspiration is very small, and each method of cervical priming is associated with side effects and additional inconvenience for the patient. Previous international guidelines for cervical priming have been published, including recommendations from the World Health Organization (WHO) and the Royal College of Obstetricians and Gynaecologists (RCOG). WHO recommends cervical preparation prior to surgical abortion for all pregnancies of 12 to 14 weeks' gestation. The guidelines note that cervical preparation may be considered for women at any gestational age, in particular those at high risk for cervical injury or uterine perforation, such as adolescents and women with cervical anomalies or previous cervical surgery [
      • World Health Organization
      Safe Abortion: Technical and Policy Guidance for Health Systems.
      ]. The RCOG guidelines state that cervical priming should be considered for all women in the first trimester, recommending that misoprostol 400 mcg be administered vaginally 3 h prior to surgery or sublingually 2 to 3 h prior to surgery. They note that cervical preparation is likely “particularly beneficial where risk factors for cervical injury or uterine perforation exist, such as [in] adolescents aged less than 17 years, advanced gestational age (particularly among parous women), cervical anomalies or previous surgery, or when a less experienced surgeon is operating” [
      • Royal College of Obstetricians & Gynaecologists
      The care of women requesting induced abortion.
      ].

      2. Clinical questions

      2.1 How much rigid dilation is needed to perform a suction abortion?

      There is no consensus among providers regarding the desired width of dilation. Frequently, in early first-trimester procedures (<8 weeks), no dilation is required to insert the desired cannula, especially in multiparous women. According to a survey of North American providers, approximately half report dilating the cervix to a diameter in millimeters equal to the gestational age in weeks. An additional 37% of providers dilate to 1 to 2 mm greater than the number of gestational weeks. The remainder dilates to 1 to 3 mm less than the gestational age, using a smaller cannula to evacuate the pregnancy [
      • O'Connell K.
      • Jones H.E.
      • Simon M.
      • Saporta V.
      • Paul M.
      • Lichtenberg E.S.
      First-trimester surgical abortion practices: a survey of National Abortion Federation members.
      ]. Most providers dilate the cervix incrementally, but some skip dilator sizes if the internal os is compliant [
      • Meckstroth K.
      • Paul M.
      First-trimester aspiration abortion.
      ].
      The Marie Stopes Procedure performed in some parts of the United Kingdom differs markedly from North American practices. In Marie Stopes outpatient centers, no rigid dilation or cervical priming is used for first-trimester surgical abortion [
      • Baldock S.
      Personal communication: Marie Stopes Procedure.
      ]. Marie Stopes providers employ atraumatic tenaculums, flexible cannulas and 1% lidocaine gel for local anesthesia. They use the smallest cannula size possible for a given gestation to evacuate the uterine contents (<6 weeks, 4-mm cannula; 6 to 7 weeks, 5-mm cannula; 8 to 9 weeks, 6-mm cannula; and 10 to 12 weeks, 7-mm cannula). If any dilation is necessary, cannulas of the appropriate size are employed as dilators. In rare cases, os finders are needed to ascertain the path of the cervical canal. This method has not been compared to other techniques in any clinical trials.

      2.2 What outcome measures should be used in research evaluating the advantages and disadvantages of cervical priming in first-trimester abortion?

      When evaluating cervical priming agents, important clinical outcomes are whether adequate cervical dilatation can be achieved to complete the procedure as planned and whether complications are reduced [
      • Grimes D.A.
      • Ray I.G.
      • Middleton C.J.
      Lamicel versus laminaria for cervical dilation before early second-trimester abortion: a randomized clinical trial.
      ]. Most studies have evaluated some combination of baseline cervical dilatation, need for further mechanical dilation, duration of the procedure, subjective assessment of ease of dilation, force required for dilation measured by cervical tonometer, intraoperative blood loss, premature passage of fetal or chorionic tissue, side effects (preoperative bleeding, fever, pain, nausea, vomiting and diarrhea), acceptability and complication rates [
      • Gupta J.K.
      • Johnson N.
      Should we use prostaglandins, tents or progesterone antagonists for cervical ripening before first trimester abortion?.
      ,
      • Platz-Christensen J.J.
      • Nielsen S.
      • Hamberger L.
      Is misoprostol the drug of choice for induced cervical ripening in early pregnancy termination?.
      ,
      • el-Refaey H.
      • Calder L.
      • Wheatley D.N.
      • Templeton A.
      Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost.
      ,
      • Lawrie A.
      • Penney G.
      • Templeton A.
      A randomised comparison of oral and vaginal misoprostol for cervical priming before suction termination of pregnancy.
      ,
      • Aronsson A.
      • Helstrom L.
      • Gemzell-Danielsson K.
      Sublingual compared with oral misoprostol for cervical dilatation prior to vacuum aspiration: a randomized comparison.
      ,
      • Ashok P.W.
      • Hamoda H.
      • Nathani F.
      • Flett G.M.
      • Templeton A.
      Randomised controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy.
      ,
      • Bugalho A.
      • Bique C.
      • Almeida L.
      • Bergstrom S.
      Application of vaginal misoprostol before cervical dilatation to facilitate first-trimester pregnancy interruption.
      ,
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • Carbonell J.L.
      • Mari J.
      • Valero F.
      • Llorente M.
      • Salvador I.
      • Varela L.
      • et al.
      Sublingual versus vaginal misoprostol (400 ug) for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • Carbonell J.L.
      • Velazco A.
      • Rodriguez Y.
      • Tanda R.
      • Sánchez C.
      • Barambio S.
      • et al.
      Oral versus vaginal misoprostol for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ficicioglu C.
      • Tasdemir M.
      • Tasdemir S.
      Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation.
      ,
      • Fong Y.F.
      • Singh K.
      • Prasad R.N.
      A comparative study using two dose regimens (200 microg or 400 microg) of vaginal misoprostol for pre-operative cervical dilatation in first trimester nulliparae.
      ,
      • Golland I.M.
      • Vaughan-Williams C.A.
      • Elstein M.
      A comparison of osmotic dilators, Lamicel and Dilapan, and a prostaglandin E1 analogue, gemeprost, for ripening the cervix before legal abortion.
      ,
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.
      • Templeton A.
      A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion.
      ,
      • Kline S.B.
      • Meng H.
      • Munsick R.A.
      Cervical dilation from laminaria tents and synthetic osmotic dilators used for 6 hours before abortion.
      ,
      • Limongelli M.D.
      • Belletti F.
      • Cecere A.T.
      • Oliva L.
      • Carlomagno G.
      Vaginal misoprostol as a cervical ripening agent prior to suction curettage for first-trimester termination of pregnancy.
      ,
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ,
      • Okanlomo K.A.
      • Ngotho D.
      • Moodley J.
      Effect of misoprostol for cervical ripening prior to pregnancy interruption before twelve weeks of gestation.
      ,
      • Oppegaard K.S.
      • Abdelnoor M.
      • Nesheim B.I.
      • Jerve F.
      • Eskild A.
      The use of oral misoprostol for pre-abortion cervical priming: a randomised controlled trial of 400 versus 200 microg in first trimester pregnancies.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Comparison between the sublingual and oral route of misoprostol for pre-abortion cervical priming in first trimester abortions.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Sublingual versus vaginal route of misoprostol for cervical ripening prior to surgical termination of first trimester abortions.
      ,
      • Sharma S.
      • Refaey H.
      • Stafford M.
      • Purkayastha S.
      • Parry M.
      • Axby H.
      Oral versus vaginal misoprostol administered one hour before surgical termination of pregnancy: a randomised controlled trial.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming.
      ,
      • Tang O.S.
      • Mok K.H.
      • Ho P.C.
      A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol for preabortion cervical ripening in first-trimester pregnancy termination.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      • Dadhwal V.
      • Sharma Y.
      A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy.
      ]. Primary outcomes on which sample sizes are calculated, however, tend to be baseline cervical dilatation or force required to reach a certain diameter of dilatation. These primary outcomes illustrate only whether or not cervical priming works to soften and dilate the cervix.
      Another important outcome measure is patient-centered, the frequency of side effects and time spent waiting for the abortion procedure. Rarely are the side effects of cervical priming, and their acceptability to women is the primary objective of a study. Women generally prefer 1-day procedures to 2-day procedures and prefer misoprostol to laminaria for cervical priming [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Goldberg A.B.
      • Drey E.A.
      • Whitaker A.K.
      • Kang M.S.
      • Meckstroth K.R.
      • Darney P.D.
      Misoprostol compared with laminaria before early second-trimester surgical abortion: a randomized trial.
      ]. Most women find both the oral and vaginal routes of misoprostol acceptable [
      • Ashok P.W.
      • Hamoda H.
      • Nathani F.
      • Flett G.M.
      • Templeton A.
      Randomised controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy.
      ,
      • Carbonell J.L.
      • Velazco A.
      • Rodriguez Y.
      • Tanda R.
      • Sánchez C.
      • Barambio S.
      • et al.
      Oral versus vaginal misoprostol for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ]. The benefit of passive dilation of the cervix prior to the surgical procedure in terms of decreased operative time and improved ease of procedure must be balanced against the patient's individual circumstances, such as side effects experienced while waiting [
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ]. The frequency of side effects has varied in cervical priming trials. Often those showing no difference lack the power to detect an effect. Those that do show significant results find that the placebo arm experiences significantly fewer side effects than the misoprostol arm. Medication abortion trials have demonstrated that self-administration of vaginal misoprostol at home, or in the clinic, is acceptable to women [
      • Kiran U.
      • Amin P.
      • Penketh R.J.
      Self-administration of vaginal misoprostol after mifepristone for termination of pregnancy: Patient acceptability.
      ,
      • Kiran U.
      • Amin P.
      • Penketh R.J.
      Self-administration of misoprostol for termination of pregnancy: safety and efficacy.
      ,
      • Schaff E.A.
      • Fielding S.L.
      • Westhoff C.
      • Ellertson C.
      • Eisinger S.H.
      • Stadalius L.S.
      • et al.
      Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A randomized trial.
      ,
      • Schaff E.A.
      • Fielding S.L.
      • Westhoff C.
      Randomized trial of oral versus vaginal misoprostol 2 days after mifepristone 200 mg for abortion up to 63 days of pregnancy.
      ].
      Ideally, the efficacy of cervical priming should be defined by its impact on complication rates. Whether or not cervical priming is worth the added inconvenience and side effects depends on whether it makes the procedure safer. Given the rarity of complications with first-trimester abortion, however, only a few studies have had sufficient power to evaluate a difference in complication rates using cervical priming [
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ,
      • Hodgson J.E.
      • Portmann K.C.
      Complications of 10,453 consecutive first-trimester abortions: a prospective study.
      ,
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      World Health Organization's Task Force on Prostaglandins for Fertility Regulation. Vaginal administration of 15-methyl-PGF2 alpha methyl ester for preoperative cervical dilatation.
      ].

      2.3 Are certain women more likely to benefit from cervical priming in the first trimester?

      Immediate complications from suction abortion include uterine perforation, hemorrhage, cervical laceration (deep or superficial) and incomplete abortion. Risk factors for major complications differ according to the specific complication. For example, increasing parity is a risk factor for uterine perforation but not for cervical injury. This finding may reflect differential changes in the myometrium and cervical stroma after delivery [
      • Grimes D.A.
      • Schulz K.F.
      • Cates Jr., W.J.
      Prevention of uterine perforation during curettage abortion.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ]. The increased risk of perforation observed with higher parity may also be related to the frequency of prior cesarean deliveries, but past studies do not always specify delivery mode. A recent large WHO multicenter trial of misoprostol versus placebo in first-trimester abortion did not find that parity was associated with the rate of acute or delayed complications, although the two deep cervical tears from dilation and four uterine perforations all occurred in the parous group [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ]. Evidence for higher complication rates in adolescents is more compelling [
      • Cates Jr., W.
      • Schulz K.F.
      • Grimes D.A.
      The risks associated with teenage abortion.
      ,
      • Zhou W.
      • Nielsen G.L.
      • Moller M.
      • Olsen J.
      Short-term complications after surgically induced abortions: a register-based study of 56 117 abortions.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ]. When the effect of parity is controlled for, adolescents have a higher risk of cervical injury, especially at gestations of more than 12 weeks, than do adult women [
      • Cates Jr., W.
      • Schulz K.F.
      • Grimes D.A.
      The risks associated with teenage abortion.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ]. It appears that young age is not a proxy for nulliparity. Rather, adolescents (age ≤17) have small, physiologically immature cervices that may be more difficult to dilate than those of adult women, regardless of obstetric history [
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ]. The WHO trial cited above did not include enough adolescents to evaluate differing complication rates.
      Existing data provide evidence of an increasing risk of immediate complications as gestational age increases, even in the first trimester [
      • Bartlett L.A.
      • Berg C.J.
      • Shulman H.B.
      • Zane S.B.
      • Green C.A.
      • Whitehead S.
      • et al.
      Risk factors for legal induced abortion-related mortality in the United States.
      ,
      • Grimes D.A.
      • Schulz K.F.
      • Cates Jr., W.J.
      Prevention of uterine perforation during curettage abortion.
      ,
      • Bozorgi N.
      Statistical analysis of first-trimester pregnancy terminations in an ambulatory surgical center.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ,
      • Child T.J.
      • Thomas J.
      • Rees M.
      • MacKenzie I.Z.
      Morbidity of first trimester aspiration termination and the seniority of the surgeon.
      ,
      • Buehler J.W.
      • Schulz K.F.
      • Grimes D.A.
      • Hogue C.J.
      The risk of serious complications from induced abortion: do personal characteristics make a difference?.
      ]. Because studies differed in their reference groups, categories of gestational age and whether or not second-trimester procedures were included, they provide no clear evidence to guide decisions about when cervical priming should begin [
      • Kapp N.
      • Lohr P.A.
      • Ngo T.D.
      • Hayes J.L.
      Cervical preparation for first trimester surgical abortion.
      ]. Taken together, however, these studies suggest that the risk of complications increases after 9 weeks, accelerating at 12 and 13 weeks' gestation. Published data are insufficient to support any comment on the risk of complications specifically in women with prior cervical conization, cesarean section or cervical stenosis or in women who are obese or have acutely anteflexed or retroflexed uteri [
      • Hakim-Elahi E.
      • Tovell H.M.
      • Burnhill M.S.
      Complications of first-trimester abortion: a report of 170,000 cases.
      ,
      • Pridmore B.R.
      • Chambers D.G.
      Uterine perforation during surgical abortion: a review of diagnosis, management, and prevention.
      ].
      In sum, women late in the first trimester and adolescents are more likely to benefit from cervical priming. Women with uterine anomalies or known cervical stenosis might also benefit [
      • Kaunitz A.M.
      • Rovira E.Z.
      • Grimes D.A.
      • Schulz K.F.
      Abortions that fail.
      ].

      2.4 Are osmotic dilators safe and effective for cervical priming in the first trimester, and which type is preferred?

      The insertion of one medium laminaria effectively dilates the cervix to at least 9 mm in more than 75% of women, reducing the need for rigid dilation [
      • Hale R.W.
      • Pion R.J.
      Laminaria: an underutilized clinical adjunct.
      ,
      • Golditch I.M.
      • Glasser M.H.
      The use of laminaria tents for cervical dilatation prior to vacuum aspiration abortion.
      ,
      • Niswander K.R.
      Laminaria tents as an aid in suction abortion.
      ,
      • Hern W.M.
      Laminaria in abortion. Use in 1368 patients in first trimester.
      ,
      • Eaton C.J.
      • Cohn F.
      • Bollinger C.C.
      Laminaria tent as a cervical dilator prior to aspiration-type therapeutic abortion.
      ,
      • Bryman I.
      • Granberg S.
      • Norstrom A.
      Reduced incidence of postoperative endometritis by the use of Laminaria tents in connection with first trimester abortion.
      ]. The dilatation achieved with laminaria tents increases with the number of tents used and with gestational age [
      • Kline S.B.
      • Meng H.
      • Munsick R.A.
      Cervical dilation from laminaria tents and synthetic osmotic dilators used for 6 hours before abortion.
      ,
      • Munsick R.A.
      • Fineberg N.S.
      Cervical dilation from multiple laminaria tents used for abortion.
      ]. Laminaria show some effect after 4 h, but more time is necessary for them to induce prostaglandin release and reach their maximum diameter [
      • Eaton C.J.
      • Cohn F.
      • Bollinger C.C.
      Laminaria tent as a cervical dilator prior to aspiration-type therapeutic abortion.
      ,
      • Manabe Y.
      • Mori T.
      • Yoshida Y.
      Decidual morphology and F prostaglandin in amniotic fluid in stretch-induced abortion.
      ]. The diameter of each laminaria tent increases by 25% if left in place for 4 h and by 90% if left in place overnight [
      • Eaton C.J.
      • Cohn F.
      • Bollinger C.C.
      Laminaria tent as a cervical dilator prior to aspiration-type therapeutic abortion.
      ,
      • Krammer J.
      • O'Brien W.F.
      Mechanical methods of cervical ripening.
      ]. The use of laminaria prior to first-trimester surgical abortion, in certain clinical settings, decreases the incidence of cervical lacerations and, to a lesser extent, uterine perforations [
      • Cates Jr., W.
      • Schulz K.F.
      • Grimes D.A.
      The risks associated with teenage abortion.
      ,
      • Grimes D.A.
      • Schulz K.F.
      • Cates Jr., W.J.
      Prevention of uterine perforation during curettage abortion.
      ,
      • Schulz K.F.
      • Grimes D.A.
      • Cates Jr., W.
      Measures to prevent cervical injury during suction curettage abortion.
      ,
      • Hale R.W.
      • Pion R.J.
      Laminaria: an underutilized clinical adjunct.
      ].
      Bokstrom and Wiqvist [
      • Bokstrom H.
      • Wiqvist N.
      Preoperative dilatation of the cervix at legal abortion with a synthetic, fast-swelling hygroscopic tent.
      ] studied the use of Dilapan for cervical priming in women from weeks 10 to 12 of gestation. They found that a 3-mm Dilapan achieved 8 mm of dilatation at 3 to 4 h and 10 mm of dilatation at 16 to 20 h, while a 4-mm Dilapan reached 8.5 mm and 11.3 mm of dilatation, respectively. The additional dilation gained with the longer duration of retention might not be clinically significant in the first trimester.
      Lamicel similarly swells rapidly, and its administration 4 h preoperatively is as effective as 16 h at increasing baseline cervical dilatation [
      • Nicolaides K.H.
      • Welch C.C.
      • Koullapis E.N.
      • Filshie G.M.
      Cervical dilatation by Lamicel--studies on the mechanism of action.
      ]. In fact, studies indicate that the total force required for dilation drops rapidly after 2 h of Lamicel placement and then plateaus [
      • Skjeldestad F.E.
      • Tuveng J.
      Cervical dilatation with Lamicel in first trimester therapeutic abortion.
      ]. One randomized trial of 629 women showed that Lamicel achieved a higher mean dilation than placebo (8.2 mm vs. 5.8 mm, p<0.001). However, the study failed to show that priming with Lamicel significantly reduced the rates of uterine perforation, infection or recurettage. However, the perforation rate in the Lamicel group was 0.4% versus 1.7% in the control group (nonsignificant), and the study may not have had sufficient power to detect a difference in complication rates [
      • Skjeldestad F.E.
      • Tuveng J.
      Cervical dilatation with Lamicel in first trimester therapeutic abortion.
      ].
      All types of osmotic dilators have advantages and disadvantages. Investigators have conducted a number of comparative trials testing their efficacy for cervical priming before first-trimester surgical abortion. Randomized trials have demonstrated that one Dilapan™ device outperforms a similar diameter laminaria with 4 h of use, but the two are equivalent at 6 h [
      • Kline S.B.
      • Meng H.
      • Munsick R.A.
      Cervical dilation from laminaria tents and synthetic osmotic dilators used for 6 hours before abortion.
      ,
      • Darney P.D.
      • Dorward K.
      Cervical dilation before first-trimester elective abortion: a controlled comparison of meteneprost, laminaria, and hypan.
      ]. A recent trial of Dilapan-S compared with 400 mcg of buccal misoprostol 3 to 4 h prior to surgical abortion at 12 to 15 weeks showed similar baseline cervical dilation (10.8 mm vs. 10.2 mm, p=0.065) [
      • Bartz D.
      • Maurer R.
      • Allen R.H.
      • Fortin J.
      • Kuang B.
      • Goldberg A.B.
      Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial.
      ]. There is a trend toward more cramping and difficult removals with Dilapan and laminaria than with Lamicel. Some surgeons report anecdotally that combining Dilapan with laminaria makes removal easier [
      • Meckstroth K.
      • Paul M.
      First-trimester aspiration abortion.
      ]; however, no evidence is available in the literature to support this practice. Finally, case reports of breakage, entrapment and displacement into the uterine cavity have involved both Dilapan and laminaria but not Lamicel [
      • Borgatta L.
      • Barad D.
      Prolonged retention of laminaria fragments: an unusual complication of laminaria usage.
      ,
      • Liang S.T.
      • Woo J.S.
      • Tang G.W.
      Ultrasonic localization of a displaced laminaria tent.
      ,
      • Hern W.M.
      Laminaria versus Dilapan osmotic cervical dilators for outpatient dilation and evacuation abortion: randomized cohort comparison of 1001 patients.
      ]. Since the release of the reformulated version, however, Dilapan-S has not been associated with these adverse events [
      • Canvin J.
      Personal communication.
      ].
      Important characteristics of osmotic dilators include convenience and side effects as well as effectiveness. The evidence indicates that Dilapan-S is superior to laminaria for short treatment periods (4 h) but that laminaria would achieve the same dilatation if allowed more time (at least 6 h). It also appears that Dilapan-S and multiple laminaria are superior to Lamicel for any given duration of time in causing wider initial dilatation [
      • Grimes D.A.
      • Ray I.G.
      • Middleton C.J.
      Lamicel versus laminaria for cervical dilation before early second-trimester abortion: a randomized clinical trial.
      ,
      • Wells E.C.
      • Hulka J.F.
      Cervical dilation: a comparison of Lamicel and Dilapan.
      ]. However, the ability to subsequently achieve the desired dilation easily with rigid dilators is comparable with all three methods. Therefore, a same-day procedure could more easily be accomplished with Dilapan-S or Lamicel than with laminaria. One Lamicel is approximately twice the cost of one Dilapan-S, and in turn, one Dilapan-S is twice the cost of one laminaria [
      • Canvin J.
      Personal communication.
      ]. However, multiple laminaria are often required to achieve the same dilation as one Lamicel or one Dilapan-S [
      • Grimes D.A.
      • Ray I.G.
      • Middleton C.J.
      Lamicel versus laminaria for cervical dilation before early second-trimester abortion: a randomized clinical trial.
      ]. To date, no published studies comparing Dilapan-S or Lamicel with a placebo have been large enough to detect a difference in complication rates.

      2.5 Is misoprostol safe and effective for cervical priming in the first trimester?

      Several randomized trials have compared misoprostol and placebo or no therapy for cervical priming before first-trimester surgical abortion and found that misoprostol increases baseline dilation and facilitates further dilation. These studies analyzed vaginal doses of 100 to 750 mcg [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • el-Refaey H.
      • Calder L.
      • Wheatley D.N.
      • Templeton A.
      Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost.
      ,
      • Bugalho A.
      • Bique C.
      • Almeida L.
      • Bergstrom S.
      Application of vaginal misoprostol before cervical dilatation to facilitate first-trimester pregnancy interruption.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ficicioglu C.
      • Tasdemir M.
      • Tasdemir S.
      Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation.
      ,
      • Limongelli M.D.
      • Belletti F.
      • Cecere A.T.
      • Oliva L.
      • Carlomagno G.
      Vaginal misoprostol as a cervical ripening agent prior to suction curettage for first-trimester termination of pregnancy.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Okanlomo K.A.
      • Ngotho D.
      • Moodley J.
      Effect of misoprostol for cervical ripening prior to pregnancy interruption before twelve weeks of gestation.
      ,
      • Wiebe E.R.
      • Rawling M.J.
      Vaginal misoprostol before first trimester abortion.
      ,
      • Mittal S.
      • Sehgal R.
      • Aggarwal S.
      • Aruna J.
      • Bahadur A.
      • Kumar G.
      Cervical priming with misoprostol before manual vacuum aspiration versus electric vacuum aspiration for first-trimester surgical abortion.
      ], oral doses of 400 to 600 mcg [
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ,
      • Edwards D.
      • Aitken R.
      • Begg A.
      • MacKay P.
      • Marchant R.
      Predilatation of the cervix before suction curettage for therapeutic abortion in early pregnancy.
      ] and a sublingual dose of 400 mcg [
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol for preabortion cervical ripening in first-trimester pregnancy termination.
      ,
      • Sharma M.
      Sublingual misoprostol for cervical priming in surgical first trimester pregnancy termination.
      ]. Almost all of these studies demonstrated an increased baseline cervical dilatation with misoprostol, and some also found a greater subjective ease of dilation [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ,
      • Mittal S.
      • Sehgal R.
      • Aggarwal S.
      • Aruna J.
      • Bahadur A.
      • Kumar G.
      Cervical priming with misoprostol before manual vacuum aspiration versus electric vacuum aspiration for first-trimester surgical abortion.
      ,
      • Edwards D.
      • Aitken R.
      • Begg A.
      • MacKay P.
      • Marchant R.
      Predilatation of the cervix before suction curettage for therapeutic abortion in early pregnancy.
      ,
      • Sharma M.
      Sublingual misoprostol for cervical priming in surgical first trimester pregnancy termination.
      ], lower measured cumulative force with dilation [
      • el-Refaey H.
      • Calder L.
      • Wheatley D.N.
      • Templeton A.
      Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ], shorter procedure time [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • Bugalho A.
      • Bique C.
      • Almeida L.
      • Bergstrom S.
      Application of vaginal misoprostol before cervical dilatation to facilitate first-trimester pregnancy interruption.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ficicioglu C.
      • Tasdemir M.
      • Tasdemir S.
      Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol for preabortion cervical ripening in first-trimester pregnancy termination.
      ] or lower estimated blood loss [
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol for preabortion cervical ripening in first-trimester pregnancy termination.
      ]. The majority of studies measured baseline cervical dilation with Hegar dilators, but a few used a cervical tonometer to measure the force required for cervical dilation. Many of these studies reported more cramping (although mild) with misoprostol than with placebo [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ficicioglu C.
      • Tasdemir M.
      • Tasdemir S.
      Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ,
      • Edwards D.
      • Aitken R.
      • Begg A.
      • MacKay P.
      • Marchant R.
      Predilatation of the cervix before suction curettage for therapeutic abortion in early pregnancy.
      ]. In general, differences between misoprostol and placebo in terms of operative time and blood loss are statistically, but not clinically, significant. The effectiveness of misoprostol is not influenced by whether manual vacuum aspiration or electric suction is used [
      • Mittal S.
      • Sehgal R.
      • Aggarwal S.
      • Aruna J.
      • Bahadur A.
      • Kumar G.
      Cervical priming with misoprostol before manual vacuum aspiration versus electric vacuum aspiration for first-trimester surgical abortion.
      ].
      In the largest trial to date, the WHO randomized 4972 women in 14 countries to either 400 mcg of misoprostol or placebo vaginally 3 h prior to surgical abortion up to 12 0/7 weeks of pregnancy [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ]. In the misoprostol arm, there was a reduced risk of superficial damage to the cervix due to tenaculum tears [3 vs. 12, relative risk (RR): 0.25, 95% confidence interval (CI): 0.07–0.89]. Only 2 of 14 study sites reported this complication, which suggests that it may be related to provider experience or technique. There was no difference in the risk of deeper cervical tears due to dilation or uterine perforation between the two groups [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ]. The risk of the delayed complication of incomplete abortion with or without the need for recurettage was lower in the misoprostol arm than in the placebo arm (19/2427 vs. 55/2431, RR: 0.35 95% CI: 0.21–0.58) [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ]. The investigators attributed this difference to (a) the ability of providers to use larger cannula sizes for procedures in the misoprostol arm, thus facilitating evacuation of the uterus and (b) a larger cervical diameter postprocedure, which eased emptying of the cavity of any retained products of conception. However, it is also possible that the reduction in incomplete abortion observed with misoprostol was due to its uterotonic effects, assisting with postprocedure expulsion of any retained tissue. Of interest, this difference was more pronounced in multiparous women.
      If misoprostol is used for cervical priming and the woman is unable to undergo surgical abortion as planned, then she is at some risk for expelling the pregnancy and theoretically a risk of congenital anomalies should she continue the pregnancy. Therefore, before receiving misoprostol, all women should give informed consent for the abortion procedure and be adequately screened by appropriately trained personnel.

      2.6 What is the optimal misoprostol regimen?

      2.6.1 Vaginal administration

      For vaginal dosing, randomized trials have found that 200 mcg is inferior to 400 mcg in terms of baseline cervical dilatation [
      • Fong Y.F.
      • Singh K.
      • Prasad R.N.
      A comparative study using two dose regimens (200 microg or 400 microg) of vaginal misoprostol for pre-operative cervical dilatation in first trimester nulliparae.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Vaginal misoprostol for pre-abortion cervical priming: is there an optimal evacuation time interval?.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Evacuation interval after vaginal misprostol for preabortion cervical priming: a randomized trial.
      ]. Studies that increased the dose to 600 or 800 mcg demonstrated increased rates of such side effects as abdominal pain, bleeding and fever [
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Evacuation interval after vaginal misprostol for preabortion cervical priming: a randomized trial.
      ], with minimal gain in cervical dilatation. Other studies have changed the regimen from an interval of 3 h and a dose of 400 mcg of vaginal misoprostol to an interval of 2 h and a dose of 600 mcg or 800 mcg to determine whether higher doses of vaginal misoprostol could dilate the cervix more rapidly. Subjects experienced more vaginal bleeding (25% vs. 17%), abdominal pain (50% vs. 13%), fever (12% vs. 0%) and less cervical dilatation with the 600-mcg dose given 2 h before the procedure than with the 400-mcg dose given 3 h before the procedure [
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Vaginal misoprostol for pre-abortion cervical priming: is there an optimal evacuation time interval?.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Evacuation interval after vaginal misprostol for preabortion cervical priming: a randomized trial.
      ]. This effect was even more pronounced with the 800-mcg dose. Other studies of 400-mcg vaginal misoprostol have shown that no effect is seen 1 h after use and that the peak effect is achieved between 3 and 4 h after use [
      • Sharma S.
      • Refaey H.
      • Stafford M.
      • Purkayastha S.
      • Parry M.
      • Axby H.
      Oral versus vaginal misoprostol administered one hour before surgical termination of pregnancy: a randomised controlled trial.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Vaginal misoprostol for pre-abortion cervical priming: is there an optimal evacuation time interval?.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Evacuation interval after vaginal misprostol for preabortion cervical priming: a randomized trial.
      ]. No additional dilation is gained from administering vaginal misoprostol more than 4 h preoperatively [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Burnett M.A.
      • Corbett C.A.
      • Gertenstein R.J.
      A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in first trimester surgical abortion.
      ]. Intervals of more than 4 h only increase the frequency of bleeding and passage of products of conception prior to scheduled curettage [
      • Burnett M.A.
      • Corbett C.A.
      • Gertenstein R.J.
      A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in first trimester surgical abortion.
      ]. Thus, 400 mcg of vaginal misoprostol given 3 to 4 h before the procedure appears to be the optimal regimen for achieving adequate dilation.

      2.6.2 Oral administration

      In the case of oral administration, results of studies examining different doses of misoprostol are inconsistent, likely because of the varied methods used to define success. One trial that compared 200 mcg and 400 mcg of oral misoprostol the night before the procedure showed that the 400-mcg dose resulted in statistically greater baseline cervical dilatation than the 200-mcg dose; however, the difference was not felt to be clinically significant [
      • Oppegaard K.S.
      • Abdelnoor M.
      • Nesheim B.I.
      • Jerve F.
      • Eskild A.
      The use of oral misoprostol for pre-abortion cervical priming: a randomised controlled trial of 400 versus 200 microg in first trimester pregnancies.
      ]. Another trial comparing 200 mcg and 400 mcg of oral misoprostol 3 h prior to the procedure found that the higher dose resulted in greater baseline cervical dilatation, as measured by cervical tonometer but no difference in the cumulative force required to dilate the cervix to 8 mm [
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ]. The optimal time between oral misoprostol administration and the procedure is unclear. Studies show that oral misoprostol is more effective than placebo when given at least 3 to 20 h prior to the procedure [
      • Bokstrom H.
      • Atterfelt P.
      • Alexandersson M.
      • Brannstrom M.
      • Norstrom A.
      Preoperative cervical softening before first trimester legal abortion by mifepristone and misoprostol: a double-blind, randomized, clinical, biochemical, and immunohistochemical study.
      ,
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Ngai S.W.
      • Tang O.S.
      • Lao T.
      • Ho P.C.
      • Ma H.K.
      Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy.
      ]. One study determined that 600 mcg of misoprostol resulted in equivalent baseline dilation at 10 and 17 h prior to procedure, but administration 10 h before the procedure was associated with fewer side effects [
      • Platz-Christensen J.J.
      • Nielsen S.
      • Hamberger L.
      Is misoprostol the drug of choice for induced cervical ripening in early pregnancy termination?.
      ]. Cervical priming with oral misoprostol most likely requires a dose of 400 to 600 mcg and a longer preoperative interval than is needed with vaginal administration for maximum effectiveness.

      2.6.3 Sublingual administration

      For sublingual dosing, one randomized trial has shown that 400 mcg is superior to 200 mcg at both 2 and 3 h prior to procedure when efficacy is measured by cervical dilation [
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol before first trimester abortion: a comparative study using two dose regimens.
      ]. However, women using the 400-mcg dose experienced more side effects. With the 400-mcg dose, increasing the time interval from 2 h to 3 h did not offer any advantages [
      • Vimala N.
      • Mittal S.
      • Kumar S.
      Sublingual misoprostol before first trimester abortion: a comparative study using two dose regimens.
      ]. Similarly, a randomized controlled trial evaluated 200 mcg, 400 mcg and 600 mcg of sublingual misoprostol prior to first-trimester suction curettage in 90 nulliparous women. The primary outcome was the ease of the procedure as reported by the provider. The 600-mcg dose of misoprostol was the most effective, with 23.3% of the cases rated as extremely easy, compared with 10% in the 400-mcg arm and 0% in the 200-mcg arm. However, among the 27 women with an embryonic or fetal demise, 33.3% in the 400-mcg group and 77.7% in the 600-mcg group delivered prior to surgery. In addition, the incidence of each side effect examined — abdominal pain, vaginal bleeding, nausea, vomiting, chills, shivering, fatigue, dizziness, headache and diarrhea— was higher in the women administered 600 mcg. This study concluded that 400 mcg was the dose that balanced efficacy and side effects. In sum, a 400-mcg dose 2 to 3 h preoperatively appears to be the optimal sublingual dosing strategy.

      2.6.4 Buccal

      The first study to evaluate buccal misoprostol for cervical priming prior to first-trimester abortion was a retrospective cohort study from Chicago [
      • Panchal H.B.
      • Godfrey E.M.
      • Patel A.
      Buccal misoprostol for cervical ripening prior to first trimester abortion.
      ]. Researchers examined the records of 685 women undergoing surgical abortion between 6 and 13 6/7 weeks who received 400 mcg of misoprostol 1 to 2 h before the procedure. Adequate dilation was measured by the provider's ability to perform the abortion without the need for further mechanical dilation with a cannula size that equaled the gestational age (e.g., 9 mm for 9 weeks). Adequate dilation was achieved in 44.2% of patients overall. Adequacy was higher in earlier gestational ages with 58.2% adequate among women 6 to 7 weeks and 22.4% among women 12 to 13 weeks. In addition, multiparous women were more likely to have adequate dilation than nulliparous women.

      2.6.5 Comparisons

      Clinical trials comparing different routes of misoprostol administration have shown mixed results. Oral and vaginal administration have been widely compared. Studies favoring vaginal administration have shown that 400 mcg produced baseline dilatation superior to the same dose given orally [
      • Carbonell J.L.
      • Velazco A.
      • Rodriguez Y.
      • Tanda R.
      • Sánchez C.
      • Barambio S.
      • et al.
      Oral versus vaginal misoprostol for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ]. Vaginal administration also resulted in less severe side effects than oral administration including abdominal pain (46% vs. 55%), nausea (1.8% vs. 17%) and vomiting (1.3% vs. 7.8%) [
      • Carbonell J.L.
      • Velazco A.
      • Rodriguez Y.
      • Tanda R.
      • Sánchez C.
      • Barambio S.
      • et al.
      Oral versus vaginal misoprostol for cervical priming in first-trimester abortion: a randomized trial.
      ]. In addition, vaginal administration was found to be more effective than oral administration later in the first trimester and in multiparous women [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Oppegaard K.S.
      • Qvigstad E.
      • Nesheim B.I.
      Oral versus self-administered vaginal misoprostol at home before surgical termination of pregnancy: a randomised controlled trial.
      ]. However, other studies have shown no difference between vaginal and oral administration [
      • Ashok P.W.
      • Hamoda H.
      • Nathani F.
      • Flett G.M.
      • Templeton A.
      Randomised controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy.
      ,
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Inal M.M.
      • Ertopcu K.
      • Arici A.
      • Ozelmas I.
      The effect of oral versus vaginal misoprostol on cervical dilatation in first-trimester abortion: a double-blind, randomized study.
      ]. Such studies have shown that 400 mcg of oral misoprostol produced equivalent dilatation at 3 h to 400-mcg vaginal dosing, all with similar side effects. A randomized controlled trial from Scotland involving 64 women showed that 400 mcg of oral misoprostol was equivalent for cervical priming to 400 mcg of vaginal misoprostol when taken 2 to 4 h before surgery [
      • Ashok P.W.
      • Hamoda H.
      • Nathani F.
      • Flett G.M.
      • Templeton A.
      Randomised controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy.
      ]. The study was powered to detect a 0.75 Newton difference in the cumulative force required to dilate the cervix. However, subjects were exposed to the vaginal misoprostol for a significantly shorter period of time than the oral misoprostol (2.3 h vs. 3.5 h) because of clinic logistics. A Cochrane meta-analysis of two studies demonstrated that, compared to oral administration, the vaginal route was associated with significantly greater initial cervical dilation [
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Kapp N.
      • Lohr P.A.
      • Ngo T.D.
      • Hayes J.L.
      Cervical preparation for first trimester surgical abortion.
      ].
      Three studies have shown that 400 mcg of sublingual misoprostol is more effective than 400 mcg of oral misoprostol given 3 h prior to procedure in terms of baseline cervical dilatation and the force required for cervical dilation greater than 7 mm [
      • Aronsson A.
      • Helstrom L.
      • Gemzell-Danielsson K.
      Sublingual compared with oral misoprostol for cervical dilatation prior to vacuum aspiration: a randomized comparison.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Comparison between the sublingual and oral route of misoprostol for pre-abortion cervical priming in first trimester abortions.
      ,
      • Saxena P.
      • Sarda N.
      • Salhan S.
      • Nandan D.
      A randomised comparison between sublingual, oral and vaginal route of misoprostol for pre-abortion cervical ripening in first-trimester pregnancy termination under local anaesthesia.
      ]. Sublingual administration has been shown to be either equivalent to or better than vaginal administration when 400 mcg is given 1 to 4 h preprocedure [
      • Carbonell J.L.
      • Mari J.
      • Valero F.
      • Llorente M.
      • Salvador I.
      • Varela L.
      • et al.
      Sublingual versus vaginal misoprostol (400 ug) for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.
      • Templeton A.
      A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Sublingual versus vaginal route of misoprostol for cervical ripening prior to surgical termination of first trimester abortions.
      ,
      • Tang O.S.
      • Mok K.H.
      • Ho P.C.
      A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      • Dadhwal V.
      • Sharma Y.
      A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy.
      ,
      • Saxena P.
      • Sarda N.
      • Salhan S.
      • Nandan D.
      A randomised comparison between sublingual, oral and vaginal route of misoprostol for pre-abortion cervical ripening in first-trimester pregnancy termination under local anaesthesia.
      ,
      • Shetty J.
      • Chawla R.
      • Pandey D.
      • Kamath A.
      • Guddattu V.
      Sublingual misoprostol: a better choice for cervical priming before manual vacuum aspiration.
      ,
      • Parveen S.
      • Khateeb Z.A.
      • Mufti S.M.
      • Shah M.A.
      • Tandon V.R.
      • Hakak S.
      • et al.
      Comparison of sublingual, vaginal, and oral misoprostol in cervical ripening for first trimester abortion.
      ]; however, it is associated with significantly more nausea (12.4% vs. 2.5%), vomiting (10.1% vs. 3.8%) and diarrhea (26.4% vs. 7.6%) [
      • Carbonell J.L.
      • Mari J.
      • Valero F.
      • Llorente M.
      • Salvador I.
      • Varela L.
      • et al.
      Sublingual versus vaginal misoprostol (400 ug) for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.
      • Templeton A.
      A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      • Dadhwal V.
      • Sharma Y.
      A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy.
      ]. Nonetheless, sublingual administration is associated with high patient and staff acceptability [
      • Carbonell J.L.
      • Mari J.
      • Valero F.
      • Llorente M.
      • Salvador I.
      • Varela L.
      • et al.
      Sublingual versus vaginal misoprostol (400 ug) for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Sublingual versus vaginal route of misoprostol for cervical ripening prior to surgical termination of first trimester abortions.
      ,
      • Tang O.S.
      • Mok K.H.
      • Ho P.C.
      A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester.
      ,
      • Saxena P.
      • Sarda N.
      • Salhan S.
      • Nandan D.
      A randomised comparison between sublingual, oral and vaginal route of misoprostol for pre-abortion cervical ripening in first-trimester pregnancy termination under local anaesthesia.
      ]. One study showed that 200 mcg of sublingual misoprostol given 2 h preoperatively was equivalent to 400 mcg of vaginal misoprostol given 3 h preoperatively in terms of cervical dilation [
      • Caliskan E.
      • Filiz T.
      • Yucesoy G.
      • Coskun E.
      • Vural B.
      • Corakci A.
      Sublingual versus vaginal misoprostol for cervical ripening PRIOR TO manual vacuum aspiration under local anaesthesia: a randomized study.
      ]. A Cochrane meta-analysis comparing sublingual to vaginal misoprostol favored the sublingual route, which was associated with less need for further dilation (RR: 1.41, 95% CI: 1.15–1.73) [
      • Carbonell J.L.
      • Mari J.
      • Valero F.
      • Llorente M.
      • Salvador I.
      • Varela L.
      • et al.
      Sublingual versus vaginal misoprostol (400 ug) for cervical priming in first-trimester abortion: a randomized trial.
      ,
      • Hamoda H.
      • Ashok P.W.
      • Flett G.M.
      • Templeton A.
      A randomized controlled comparison of sublingual and vaginal administration of misoprostol for cervical priming before first-trimester surgical abortion.
      ,
      • Tang O.S.
      • Mok K.H.
      • Ho P.C.
      A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester.
      ,
      • Vimala N.
      • Mittal S.
      • Kumar S.
      • Dadhwal V.
      • Sharma Y.
      A randomized comparison of sublingual and vaginal misoprostol for cervical priming before suction termination of first-trimester pregnancy.
      ,
      • Kapp N.
      • Lohr P.A.
      • Ngo T.D.
      • Hayes J.L.
      Cervical preparation for first trimester surgical abortion.
      ]. However, the sublingual route was associated with a higher occurrence of nausea [
      • Kapp N.
      • Lohr P.A.
      • Ngo T.D.
      • Hayes J.L.
      Cervical preparation for first trimester surgical abortion.
      ]. Routes other than vaginal administration of misoprostol have been favored because of concern about the uniformity of vaginal absorption of misoprostol. In addition, data indicate that some women prefer to take misoprostol tablets by mouth to avoid a vaginal examination or vaginal self-administration of misoprostol [
      • Saxena P.
      • Sarda N.
      • Salhan S.
      • Nandan D.
      A randomised comparison between sublingual, oral and vaginal route of misoprostol for pre-abortion cervical ripening in first-trimester pregnancy termination under local anaesthesia.
      ,
      • Ho P.C.
      • Ngai S.W.
      • Liu K.L.
      • Wong G.C.
      • Lee S.W.
      Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy.
      ]. Buccal administration, with a pharmacokinetic and physiologic profile similar to vaginal administration, might offer the effectiveness and decreased side effects of vaginal administration combined with high acceptability for both patient and staff [
      • Meckstroth K.R.
      • Whitaker A.K.
      • Bertisch S.
      • Goldberg A.B.
      • Darney P.D.
      Misoprostol administered by epithelial routes: drug absorption and uterine response.
      ,
      • Patel A.
      • Talmont E.
      • Morfesis J.
      • Pelta M.
      • Gatter M.
      • Momtaz M.R.
      • et al.
      Adequacy and safety of buccal misoprostol for cervical preparation prior to termination of second-trimester pregnancy.
      ].
      In sum, compared with the oral route, vaginal administration is equally or more effective and is associated with fewer side effects. Self-administration of vaginal misoprostol is acceptable to most women, as shown previously in medication abortion trials [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ]. However, staff responsible for the vaginal placement of misoprostol in the clinic tend to prefer the oral or sublingual routes of administration [
      • Ashok P.W.
      • Hamoda H.
      • Nathani F.
      • Flett G.M.
      • Templeton A.
      Randomised controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy.
      ]. The sublingual route is more effective than oral administration, works faster than vaginal administration, but is associated with more side effects than either oral or vaginal administration.

      2.7 How does misoprostol compare to osmotic dilators for cervical priming?

      Two randomized controlled trials have compared misoprostol to laminaria for cervical priming before surgical abortion at 7 to 14 weeks. One trial compared 400 mcg of oral or vaginal misoprostol to one medium laminaria for 4 h prior to the suction aspiration [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ]. Vaginal misoprostol significantly outperformed oral misoprostol in mean cervical dilatation (28.0 mm ± 7.3 vs. 24.2 mm ± 4.8). The mean cervical dilatation with laminaria (25.9 mm ± 5.8) was less than with vaginal misoprostol but greater than with oral misoprostol. Still, neither comparison reached significance, primarily because of inadequate statistical power. The groups did not differ in the proportion of subjects requiring additional dilation, the difficulty of additional dilation, amount of blood loss or the duration of the procedure. The women who received laminaria experienced significantly more discomfort with insertion than did those using oral or vaginal misoprostol. Groups were equivalent in level of pain during the waiting period and requests for pain medication. Overall acceptability of the method of dilation was greater than 90% in each group and was not significantly different among groups. The study authors concluded that vaginal misoprostol was preferable because of its efficacy, ease of use and lack of major side effects.
      The second trial compared one 3-mm laminaria tent to 200 mcg of vaginal misoprostol, both administered the day prior to the procedure (19 to 26 h) [
      • Burnett M.A.
      • Corbett C.A.
      • Gertenstein R.J.
      A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in first trimester surgical abortion.
      ]. This Canadian study found that laminaria achieved greater baseline cervical dilatation than vaginal misoprostol (35 mm vs. 28 mm, p<0.001). There was no difference in operative times or ease of dilation between the two groups. The women who received laminaria reported significantly more pain with insertion, but the women using misoprostol had significantly more bleeding in the hours between the insertion and the procedure. Two subjects who received misoprostol passed pregnancy tissue before their scheduled curettage. Nevertheless, significantly more women said they would prefer misoprostol for cervical dilation if they had an abortion in the future.
      A third study compared 400 mcg of buccal misoprostol with a single 4-mm Dilapan-S 3 to 4 h prior to surgical abortion between 12 0/7 and 15 0/7 weeks [
      • Bartz D.
      • Maurer R.
      • Allen R.H.
      • Fortin J.
      • Kuang B.
      • Goldberg A.B.
      Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial.
      ]. A total of 125 women were randomized, with a mean gestational age of 13 3/7 weeks. The study procedures required a sham dilator placement for the misoprostol arm. There was a slight difference between the treatment arms in preoperative cervical dilation (Dilapan-S, 10.8-mm diameter, vs. misoprostol, 10.2-mm diameter, p=0.065), and 95% of women in each group required further mechanical dilation. Mechanical dilation was rated as more difficult by the provider in the misoprostol arm. However, the two groups did not differ in procedure time, estimated blood loss, recovery time or acute complications. More women in the misoprostol arm than in the Dilapan-S arm experienced preoperative cramping, but the frequency of bleeding, nausea, vomiting or diarrhea did not differ. The authors concluded that both cervical priming methods were reasonable options.
      In summary, same-day vaginal misoprostol requires less time to achieve the same dilatation as overnight laminaria, is associated with less discomfort with insertion and is preferred by women. Buccal misoprostol is comparable to Dilapan-S in providing adequate dilation for same-day late first-trimester and early second-trimester abortion.

      2.8 Does cervical priming reduce pain during first-trimester surgical abortion?

      The goal of cervical priming is to make suction aspiration safer and less uncomfortable for the patient. While studies evaluating cervical priming agents often collected data on pain before, during and after the procedure, no study examined pain as a primary outcome. Discomfort with the placement of the cervical ripening agent occurs more often in women treated with laminaria than in those treated with misoprostol [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Burnett M.A.
      • Corbett C.A.
      • Gertenstein R.J.
      A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in first trimester surgical abortion.
      ]. Preoperative cramping and abdominal pain occur more frequently in women exposed to both osmotic dilators or misoprostol versus placebo [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.
      ,
      • Platz-Christensen J.J.
      • Nielsen S.
      • Hamberger L.
      Is misoprostol the drug of choice for induced cervical ripening in early pregnancy termination?.
      ,
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ,
      • Hall G.
      • Ekblom A.
      • Persson E.
      • Irestedt L.
      Effects of prostaglandin treatment and paracervical blockade on postoperative pain in patients undergoing first trimester abortion in general anesthesia.
      ]. In clinical studies, this level of pain is usually described as mild, without the need for analgesic agents [
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ,
      • de Jonge E.T.
      • Jewkes R.
      • Levin J.
      • Rees H.
      Randomised controlled trial of the efficacy of misoprostol used as a cervical ripening agent prior to termination of pregnancy in the first trimester.
      ,
      • Ficicioglu C.
      • Tasdemir M.
      • Tasdemir S.
      Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation.
      ,
      • Ngai S.W.
      • Chan Y.M.
      • Tang O.S.
      • Ho P.C.
      The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial.
      ,
      • Saxena P.
      • Salhan S.
      • Sarda N.
      Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration in first trimester interruption of pregnancy.
      ]. One study, however, found that cervical priming with prostaglandin analogues increased both preoperative and postoperative pain and the use of analgesics [
      • Hall G.
      • Ekblom A.
      • Persson E.
      • Irestedt L.
      Effects of prostaglandin treatment and paracervical blockade on postoperative pain in patients undergoing first trimester abortion in general anesthesia.
      ]. Another study showed that intraoperative pain levels were not lower with cervical priming using either vaginal or oral misoprostol than with placebo [
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ]. The higher the dose and the longer the interval of use for any cervical priming agent, the more women experienced preoperative discomfort, which might include bleeding from incomplete abortion and the distress of passing products of conception [
      • Platz-Christensen J.J.
      • Nielsen S.
      • Hamberger L.
      Is misoprostol the drug of choice for induced cervical ripening in early pregnancy termination?.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming.
      ,
      • Singh K.
      • Fong Y.F.
      • Prasad R.N.
      • Dong F.
      Evacuation interval after vaginal misprostol for preabortion cervical priming: a randomized trial.
      ,
      • Burnett M.A.
      • Corbett C.A.
      • Gertenstein R.J.
      A randomized trial of laminaria tents versus vaginal misoprostol for cervical ripening in first trimester surgical abortion.
      ]. While most trials show that cervical priming shortens operative time by reducing the need for mechanical dilation, this does not always translate into a reduction in pain as perceived by the patient [
      • Cakir L.
      • Dilbaz B.
      • Caliskan E.
      • Dede FS Dilbaz S.
      • Haberal A.
      Comparison of oral and vaginal misoprostol for cervical ripening before manual vacuum aspiration of first trimester pregnancy under local anesthesia: a randomized placebo-controlled study.
      ].
      To directly evaluate the pain experienced with misoprostol for cervical priming, one prospective cohort study followed 102 women undergoing surgical abortion between 7 and 14 weeks gestation who chose (in collaboration with their physician) either overnight laminaria or same-day misoprostol (400 mcg vaginally 3 to 4 h prior to the procedure) [
      • Gagne A.
      • Guilbert E.
      • Ouellet J.
      • Roy V.
      • Tremblay J.G.
      Assessment of pain after elective abortion relating to the use of misoprostol for dilatation of the cervix.
      ]. The study was limited by its lack of randomization, and by the greater percentage of women in the misoprostol group than in the laminaria group who were at less than 10 weeks of gestation (92% vs. 58%). Pain scores (0 to 10) at insertion were higher in the laminaria group, 4.26, than in the misoprostol group, 0.74 (p<.001). As seen in other studies, significantly more women in the misoprostol group than in the laminaria group experienced fever, chills and diarrhea, but they found the method easier to use. Right before the procedure, the pain score in the misoprostol group was 2.44, compared with 1.10 in the laminaria group (p=.002). After multivariable analysis, this effect was blunted. Although the pain control used during the procedure was not controlled and could have induced a paracervical block, nitrous oxide, fentanyl and/or midazolam, the average pain score 1 h after the procedure was 2.24 in the misoprostol group and 0.78 in the laminaria group (p<.001). This difference held after multivariable analysis with moderate to severe pain occurring postoperatively in 24% of the misoprostol group and 4.5% in the laminaria group. The authors speculate that continuing uterine contractions caused by the misoprostol contributed to the postoperative pain levels. In sum, cervical priming does not reduce pain before, during or after surgical abortion.

      2.9 Is cervical priming before first-trimester surgical abortion acceptable to women?

      Investigators have not focused on the acceptability to women of cervical priming as compared to mechanical dilation before first-trimester suction aspiration. Evidence indicating whether women prefer cervical priming is lacking. Studies have documented that women prefer same-day misoprostol to overnight laminaria [
      • MacIsaac L.
      • Grossman D.
      • Balistreri E.
      • Darney P.
      A randomized controlled trial of laminaria, oral misoprostol, and vaginal misoprostol before abortion.
      ]. One randomized controlled trial found no difference in satisfaction when comparing misoprostol to same-day Dilapan-S; however, both arms underwent a speculum exam to provide adequate blinding [
      • Bartz D.
      • Maurer R.
      • Allen R.H.
      • Fortin J.
      • Kuang B.
      • Goldberg A.B.
      Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial.
      ]. Very few placebo-controlled trials of misoprostol for cervical ripening explicitly analyzed patient acceptability. The amount of time a woman is willing to wait for cervical priming to produce its proposed benefits (shorter procedure time and decreased occurrence of rare complications) is not known. Nor is it known whether some women would choose to tolerate slightly more intraoperative pain, for a brief duration, to avoid waiting and an increased risk of unpleasant preoperative side effects, like bleeding, cramping, nausea and vomiting. The largest placebo-controlled trial to date reported that 1355 (55%) women randomized to 400-mcg vaginal misoprostol 3 h before their procedure experienced abdominal pain, compared with 545 (22%) of women randomized to the placebo arm [
      • Meirik O.
      • My Huong N.T.
      • Piaggio G.
      • Bergel E.
      • von Hertzen H.
      • Regulation WHORGoPMoF
      Complications of first-trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial.