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Cervical Ripening

  • Author: Aaron E Goldberg, MD; Chief Editor: Carl V Smith, MD  more...
 
Updated: Jan 12, 2015
 

Overview

In pregnancy, the uterine cervix serves 2 major functions. First, it retains its physical integrity by remaining firm during pregnancy as the uterus dramatically enlarges. This physical integrity is critical so that the developing fetus can remain in the uterus until the appropriate time for delivery. Second, in preparation for labor and delivery, the cervix softens and becomes more distensible, a process called cervical ripening. These chemical and physical changes are required for cervical dilation, labor and delivery of a fetus.

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Uterine Characteristics

The human uterus is composed of 2 basic parts, the fundus and the cervix. The fundus is composed of 2 layers: the myometrium and endometrium. The myometrium, which is predominantly smooth muscle cells, comprises the wall of the uterus and is the thickest layer. The endometrium, which lines the endometrial cavity, undergoes dramatic changes during the menstrual cycle. In the absence of pregnancy, it sheds down to the basal layer at the end of the cycle during menses. The normal pregnant cervix is 3.5 cm or longer and is composed predominantly of connective tissue, mainly collagen. In contrast to the fundus, it has only 10-15% smooth muscle. It changes little during the menstrual cycle and pregnancy until the onset of cervical ripening.

The human cervix consists mainly of extracellular connective tissue. The predominant molecules of this extracellular matrix are type 1 and type 3 collagen, with a small amount of type 4 collagen at the basement membrane. Intercalated among the collagen molecules are glycosaminoglycans and proteoglycans, predominantly dermatan sulfate, hyaluronic acid, and heparin sulfate. Fibronectin and elastin also run among the collagen fibers. The highest ratio of elastin to collagen is at the internal os. Both elastin and smooth muscle decrease from the internal to the external os of the cervix.

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Ripening of the Cervix

Cervical ripening refers to the softening of the cervix that typically begins prior to the onset of labor contractions and is necessary for cervical dilation and the passage of the fetus. Cervical ripening results from a series of complex biochemical processes that ends with rearrangement and realignment of the collagen molecules. The cervix thins, softens, relaxes and dilates in response to uterine contractions, allowing the cervix to easily pass over the presenting fetal part during labor.

In late pregnancy, hyaluronic acid content increases in the cervix. This leads to an increase in water molecules that intercalate among the collagen fibers. The amount of dermatan sulfate decreases, leading to reduced bridging among the collagen fibers and a corresponding decrease in cervical firmness. Chondroitin sulfate also decreases.

Cervical ripening is associated with decreased collagen fiber alignment, decreased collagen fiber strength and diminished tensile strength of the extracellular cervical matrix. An associated change with the cervical ripening process is an increase in cervical decorin (dermatan sulfate proteoglycan 2), leading to collagen fiber separation. Together, these changes lead to softening of the cervix (ie, ripening).

With uterine contractions, the ripened cervix dilates as the presenting fetal part descends, leading to reorientation of the tissue fibers in the cervix in the direction of the stress. Under the effect of myometrial contractions, the cervix passively dilates and is pulled over the presenting fetal part. Evidence also indicates that the elastin component of the cervix behaves in a ratchetlike manner so that dilation is maintained following the contraction.

In summary, cervical ripening is the result of realignment of collagen, degradation of collagen cross-linking due to proteolytic enzymes. Cervical dilation results from these processes plus uterine contractions. This is a complicated series of events in which many changes occur both simultaneously and sequentially. Research in this area is challenging due to both the difficulties inherent in human subjects research and the many differences existing between species.

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Role of Various Hormones in the Process of Cervical Ripening

A complex series of interactions occurs whereby various hormones stimulate the chemical reactions critical for cervical ripening. Associated with cervical ripening is an increase in the enzyme cyclooxygenase-2, leading to a local increase of prostaglandin E2 (PGE2) in the cervix. The increase in local PGE2 leads to a series of important changes associated with cervical ripening, including the following:

  • Dilation of small vessels in the cervix
  • Increase in collagen degradation
  • Increase in hyaluronic acid
  • Increase in chemotaxis for leukocytes, which causes increased collagen degradation
  • Increase in stimulation of interleukin (IL)–8 release

Prostaglandin F2-alpha is also involved in the process via its ability to stimulate an increase in glycosaminoglycans.

Cervical ripening is associated with increased activity of matrix metalloproteinases 2 and 9, enzymes that degrade extracellular matrix proteins. Cervical collagenase (also called matrix metalloproteinase 1) and elastase also increase. Near term, collagen turnover increases and degradation of newly synthesized collagen increases, leading to decreased collagen content in the cervix.

In animal studies, sex steroids have been demonstrated to be involved in cervical ripening. In the rat cervix, increasing estrogen leads to increased collagenase activity, cervical cell apoptosis, and eosinophil infiltration. Animal models also exhibit a decrease in receptor-mediated progesterone activity, but whether this is involved in cervical ripening is unclear.

The role of inflammatory agents in cervical ripening has also been studied. IL-8 can lead to neutrophil chemotaxis, which is associated with collagenase activity and cervical ripening. These inflammatory agents may be particularly important as mediators of cervical ripening associated with preterm labor.

Recent study has focused on the nitric oxide synthase (NOS)/nitric oxide (NO) system. The NOS/NO system has been postulated to have a regulatory role in the myometrium and cervix during pregnancy and parturition. In rat studies, NO and increased NOS activity are associated with uterine quiescence. NOS activity is higher prior to labor and decreases during labor, thereby playing a role in the onset of uterine contractions associated with labor. In rat studies, NO levels and NOS activity behave in an opposite fashion in the cervix. Prior to cervical ripening, NOS activity is low and then increases at the time of labor, associated with cervical ripening. NOS activity leading to NO production is the final pathway in inducing chemical changes associated with cervical ripening. In the human cervix, ripening is associated with an increase in induced NOS (iNOS) and brain NOS expression in the cervix.

Resident and migrating inflammatory cells can cause the increase in iNOS activity. Indeed, in the primate, cervical ripening has many aspects of an inflammatory process—tissue remodeling and breakage of chemical bridges between collagen fibers. Inflammatory agents such as IL-1, tumor necrosis factor-alpha, and IL-8 seem to be involved in cervical ripening.

NO also appears to play a role in this process because animal studies show that increased cervical NO leads to an increase in metalloproteinase activity, cellular apoptosis in the cervix, and glycosaminoglycan synthesis in the cervix. All of these changes are associated with the cervical ripening process.

NO also could play a role in premature cervical ripening associated with preterm labor, particularly in preterm labor triggered by infection. Inflammatory cells are rich in iNOS activity, leading to a dramatic increase in NO in the cervix, which stimulates the chemical changes associated with cervical ripening and leads to preterm labor and delivery. Human and animal studies support a role for NO in the process of cervical ripening. NO donors, when applied to the cervix, induce cervical ripening.

To stop preterm labor successfully, both uterine contractions and cervical ripening must be halted. Speculating that this requires blockage of prostaglandin synthesis in the uterine fundus and cervix (and local NO synthesis in the cervix) is tempting. The role that inflammatory agents play in the cervical ripening process could explain the explosive nature of the cervical changes that occur in preterm labor, particularly when associated with uterine infections.

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Evaluation of Cervical Ripening

A variety of techniques have been developed to quantify cervical ripening in order to predict the timing of labor and delivery. This quantification is useful for patients at risk for preterm labor and for helping predict which patients will respond to induction of labor for medical reasons or for postdate pregnancy.

The most commonly used methodology to evaluate cervical ripening is the Bishop score because it is simple and has the most predictive value. This score uses cervical dilation, effacement, consistency, position, and the station of the presenting part. Other methods that have been described in the literature, generally for gauging the risk of preterm labor, include ultrasound assessment of the cervix and detection of fetal fibronectin in cervicovaginal secretions.

A Bishop score of 5 or more is considered significant for cervical ripening and favorable for induction of labor. Bishop score is calculated as follows:

Dilation

See the list below:

  • For 0 cm, 0 points are scored.
  • For 1-2 cm, 1 point is scored.
  • For 3-4 cm, 2 points are scored.
  • For 5-6 cm, 3 points are scored.

Effacement

See the list below:

  • For 0-30%, 0 points are scored.
  • For 40-50%, 1 point is scored.
  • For 60-70%, 2 points are scored.
  • For 80%, 3 points are scored.

Station

See the list below:

  • For -3 station, 0 points are scored.
  • For -2 station, 1 point is scored.
  • For -1 and 0 station, 2 points are scored.
  • For +1 to +2 station, 3 points are scored.

Consistency

See the list below:

  • For firm consistency, 0 points are scored.
  • For medium consistency, 1 point is scored.
  • For soft consistency, 2 points are scored.

Position

See the list below:

  • For posterior position, 0 points are scored.
  • For mid position, 1 point is scored.
  • For anterior position, 2 points are scored.

A recent study examining over 5,600 nulliparous women undergoing induction of labor found that a simplified Bishop score, including only cervical dilation, effacement, and station, was equally as predictive as the traditional Bishop score in predicting vaginal delivery.[1]

Emerging evidence suggests that ultrasound assessment of the cervix helps distinguish patients at increased risk of preterm labor. In an meta analysis, Crane and Hutchens evaluated more than 300 studies, including 14 articles involving more than 2200 women in their final analysis. They found that ultrasound is a strong predictor of preterm birth among asymptomatic women at less than 35 weeks' gestation.[2]

Detection of fetal fibronectin in cervicovaginal secretions has also been used. Fetal fibronectin is a glycoprotein found in amniotic fluid and at the chorionic decidual interface. The absence of this protein in cervicovaginal secretions predicts prolongation of pregnancy. Fetal fibronectin is also predictive of response to prostaglandin application to the cervix at term in order to induce cervical ripening and labor. Currently, evaluation of fetal fibronectin is used predominantly in the assessment and triage of patients for preterm labor.

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Induction of Cervical Ripening

Bishop scores are somewhat subjective, but a score of less than 5 suggests further ripening is needed, while a score of 9 or greater suggests ripening is completed. No maximum has been determined for the number of doses of a cervical ripening agent that can be given. Indeed, if the patient has no pressing indication for delivery and if fetal well-being parameters are reassuring, the patient can even be discharged, to return in a few days for another attempt at induction. Good clinical judgment is indispensable. A variety of methods have been developed to induce cervical ripening in the preparation of the cervix for labor and delivery.[3]

Prostaglandins

Two forms of PGE2 (dinoprostone) are available commercially. In randomized trials, the 2 forms are equivalent in efficacy. The first is Prepidil, which is formulated as a gel and is placed inside the cervix, but not above the internal os. The application (3 g gel/0.5 mg dinoprostone) can be repeated in 6 hours, not to exceed 3 doses in 24 hours. The second is Cervidil, which contains 10 mg of dinoprostone embedded in a mesh and is placed in the posterior fornix of the vagina. This allows for controlled release of dinoprostone over 12 hours, after which it is removed.

Comparison between the use of intravenous oxytocin alone with a combination of oxytocin and either vaginal or intracervical PGE2 demonstrate that prostaglandins result in a significantly lower cesarean delivery rate and an increased proportion of vaginal deliveries within 24 hours. However, patients with ruptured membranes the time of labor induction had an increased rate of chorioamnionitis among those receiving vaginal or intracervical PGE2.[4]

Prostaglandin E1 analog (misoprostol) use has been described in a series of articles. This is a synthetic prostaglandin, which is marketed as an antiulcer agent under the trade name Cytotec. One quarter of a tablet (25 mcg), which can be crushed and placed on the cervix, has been shown in many studies to be quite effective in inducing cervical ripening and labor. The application of the medication can be repeated every 4 hours.

Two meta-analyses comparing randomized trials of vaginal misoprostol with dinoprostone found an increased rate of vaginal delivery within 24 hours and similar cesarean delivery rates in the misoprostol groups and hence conclude that misoprostol is the more effective agent.[5, 6]

Misoprostol has also been administered orally (50-100 mcg, which can be repeated every 4 h), but vaginal administration seems to be more efficacious. Vaginally administered misoprostol has been used for cervical ripening and labor induction in pregnancies complicated by oligohydramnios. In these patients, the risk for adverse perinatal outcomes was not increased compared with patients with normal amniotic fluid volumes. Note that the US Food and Drug Administration classifies Cytotec as a pregnancy category X drug. The manufacturer has been ambivalent about this off-label use of the medication, and the Food and Drug Administration only acknowledges that misoprostol is being used in pregnancy.

The American College of Obstetrics and Gynecology (ACOG) Committee on Obstetrics Practice recommends that misoprostol not be used in induction of labor after previous cesarean section or major uterine surgery, due to a significant risk of uterine rupture.[7]

The major risk of the above prostaglandin preparations is uterine hyperstimulation. The woman and fetus must be monitored for contractions, fetal well-being, and changes in the cervical Bishop score. Finally, Christensen et al demonstrate that the combination of oxytocin induction, preceded by a dinoprostone insert is safe, and this significantly shortens induction-to-delivery times.[8]

The exception to this appears to be women with prior cesarean deliveries. The ACOG Committee on Obstetric Practice, in its review of pertinent literature, notes that the sequential use of prostaglandins and oxytocin appears to increase the risk of uterine rupture in women with previous cesarean section.[7]

Balloon catheter

A 30-mL to 50-mL Foley catheter filled with saline is effective in inducing cervical ripening and dilation. The catheter is placed in the uterus, and the balloon is filled. Direct pressure is then applied to the lower segment of the uterus and the cervix. This direct pressure causes stress in the lower uterine segment and probably the local production of prostaglandins.

In some studies, the catheter is combined with a saline solution as an extra-amniotic infusion.[9] No evidence suggests that extra-amniotic saline infusion (EASI) increases the risk of chorioamnionitis.[10] A meta-analysis involving 27 studies and 3532 patients found that no difference between Foley balloon and PGE2 use in cesarean delivery rate. This study was hampered by significant heterogeneity of the studies and subgroup analysis suggested that Foley balloon in combination with oxytocin and EASI may indeed have a higher vaginal delivery rate and lower rate of tachysystole.[11]

The PROBAAT trial compared the effectiveness and safety of induction of labor using a Foley catheter with induction using vaginal prostaglandin E2 gel. They found that in women with an unfavorable cervix at term, the outcomes were similar, with fewer maternal and neonatal side-effects associated with Foley catheter use.[12]

Low-dose oxytocin infusion

In this method, a low-dose oxytocin infusion is performed, with an increase in dose from 1 to 4 mU/min. Ferguson et al showed this method to be comparable to intravaginal misoprostol for cervical priming.[13] Because of the ease of turning off the oxytocin infusion, they suggested that this method may have a preferential role in high-risk patients whose fetuses are at increased risk for intolerance of labor.

Antiprogesterone

Mifepristone (formerly known as RU 486) is an effective antiprogesterone and antiglucocorticoid that works by binding to progesterone and glucocorticoid receptors. Although individual randomized trials have shown favorable results for its use in inducing labor, a Cochrane Database review concluded that data were insufficient to support its use in labor induction. This review did note a decreased rate of cesarean delivery with mifepristone use, suggesting potential future areas of research.[14]

Hygroscopic dilators

Several products are available that can be placed in the cervix and dilated by water absorption. Laminaria are made from dried seaweed. Commercial products, Dilapan and Lamicel, are produced from synthetic hygroscopic material. Several dilators are inserted in the cervix—as many as will fit—and they expand over 12-24 hours as they absorb water. Absorption of water leads to expansion of the dilators and opening of the cervix. They probably work much the same as the balloon catheter. Women do not need prophylactic antibiotics for the balloon catheter or hygroscopic dilators, unless specific indications exist such as need for subacute bacterial endocarditis (SBE) prophylaxis.

Membrane stripping

Manual separation of the amniotic membranes from the cervix is thought to induce cervical ripening and the onset of labor. The mechanism is unknown, but mechanical disruption of this tissue has been postulated to cause an increase in local prostaglandins by the induction of phospholipase A2 in the cervical and membrane tissues. Such a postulation is certainly consistent with the known stimulation of cervical ripening by prostaglandins. However, there is no strong evidence at this time that membrane stripping significantly shortens the duration of pregnancy. Authors of a Cochrane Database review on this topic concluded that this practice provides no clinically important benefits.[15]

Nitric oxide donors

Studies are being conducted on the use of nitric oxide donors for cervical ripening with conflicting results. Preliminary small studies evaluating isosorbide mononitrate (40 mg) and glyceryl trinitrate had encouraging results. However, randomized controlled trials comparing misoprostol with and without isosorbide mononitrate have demonstrated contradictory results. Furthermore, a Cochrane Database review of 8 studies consisting of 718 patients evaluating the use of nitric oxide donors for cervical ripening in first trimester surgical abortion found them to be inferior to prostaglandins and associated with more side effects.[16, 17, 18]

A randomized, double-blind, placebo-controlled study by Schmitz et al also cast doubt on the use of nitric oxide donors in cervical ripening, finding them to be no more effective than placebo in reducing the rate of cesarean sections in nulliparous women with prolonged pregnancy. The study, of nulliparous women at 41 weeks’ gestation, included 678 patients who received vaginal isosorbide mononitrate and 684 women who received placebo, all on an outpatient basis. The investigators found that the cesarean delivery rate in the isosorbide mononitrate and placebo groups were nearly identical (27.3% vs 27.2%, respectively) and that side effects occurred more frequently in the women treated with the nitric oxide donor than in the other patients (78.8% vs 27.9%, respectively).[19]

Relaxin

Because of the results from a series of animal studies, relaxin has been predicted to have effects on cervical ripening in humans. The findings that porcine relaxin induces cervical ripening in humans supports this conclusion. Paradoxically, human relaxin has no effect on the human cervix, and relaxin is not currently used in cervical ripening or induction of labor. The reason for the species difference is unknown and calls into question the role of human relaxin in human parturition.

In addition, animal research suggests that supplemental hyaluronidase may shorten labor leading to improved induction success.[20] Future research in these areas, and others, may lead to improved cervical ripening and labor induction methods.

Summary of induction of cervical ripening

Induction of cervical ripening is critical to successful induction of labor in a pregnant patient whose cervix has not gone through the ripening process. Cervical ripening allows the uterine contractions to effectively dilate the cervix. The amount of uterine pressure required to dilate a ripe cervix is thought to be approximately 1600 mm Hg, while the pressure to dilatate an unripe cervix is estimated to be greater than 5 times that, or 10,000 mm Hg.

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Economic Burden of Mistimed Cervical Ripening

Preterm and early term labor and delivery

Accurate dating of pregnancy using early prenatal care and ultrasonography is advised before cervical ripening and induction of labor. Mistimed cervical ripening and induction can result in unplanned iatrogenic preterm birth and recent evidence documents increased neonatal morbidity in babies born prior to 39 weeks' gestation but after 37 weeks' gestation. Current ACOG guidelines recommend against elective induction of labor before 39 completed weeks of pregnancy, unless medical indications for earlier delivery are noted. Elective inductions account for about half of all inductions and 10% of deliveries.

The ACOG recommends that dating be confirmed with at least one of the following:

  • Ultrasonography dating at less than 20 weeks' gestation is consistent with gestational age of 39 weeks or more
  • Fetal heart tones have been documented in the patient's medical records for at least 30 weeks by Doppler ultrasonography
  • 36 weeks have passed since a positive urine or serum pregnancy test for human chorionic gonadotropin

In the United States, the national cost for preterm labor, undelivered, exceeds $360 million in total expenditures per year. Preterm labor hospitalization costs are in excess of $820 million. However, the direct economic cost is only a fraction of the ultimate cost of delivery of children who are preterm. The cost of immediate newborn care for preterm infants has been estimated at $5 billion annually, and long-term health costs are also very high.

Several studies have shown significant morbidity among children born prematurely. A 5-year follow-up evaluation of children born before 32 weeks' gestation showed significant language difficulties. Of children born weighing less than 1500 g, one fourth had severe or multiple psychological problems, with a significant decrease in intelligence quotient and school learning and an increase in discipline problems. A 10-year follow-up evaluation of children born before 29 weeks' gestation showed a significant increase in behavioral disorders in school and performance below grade level.

The great successes in neonatal nurseries and intensive care units have dramatically increased the ability of children who are significantly preterm to survive. However, the learning disabilities and behavioral disorders in this group are quite significant, creating an ongoing challenge for their parents, the schools, and society as a whole.

Postterm pregnancy

Postdate labor induction in a woman with an unripe cervix is also associated with difficulties. Although research has demonstrated a higher cesarean delivery rate when labor is included in the absence of a ripened cervix, once pregnancies go beyond 41 weeks' gestation, induction of labor may provide benefits.

In a meta-analysis of studies examining induction of labor versus expectant management of low-risk pregnancies, Sanchez-Ramos et al found that induction of labor at 41 weeks' gestation resulted in a lower cesarean delivery rate (20.1%) than those expectantly managed (22%) with no significant differences in perinatal morbidity.[21] Therefore, cervical ripening is advised prior to inducting labor in women with an "unfavorable" or unripened cervix.

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Contraindications to Cervical Ripening

Contraindications to cervical ripening include, but are not limited to, the following:

  • Active herpes
  • Fetal malpresentation
  • Nonreassuring fetal surveillance
  • History of prior traumatic delivery
  • Regular contractions
  • Unexplained vaginal bleeding
  • Placenta previa
  • Vasa previa
  • Prior uterine myomectomy involving the endometrial cavity or classical cesarean delivery

Previously, a history of a prior low transverse cesarean delivery was considered a contraindication to induction of labor. According to the ACOG Practice Bulletin on Vaginal Birth After Previous Cesarean Delivery, induction of labor is not contraindicated in women with a prior low transverse cesarean delivery; however, use of prostaglandins should be avoided in these patients due to a significantly increased risk of uterine rupture.[22] A relative contraindication to cervical ripening is ruptured membranes. At this time, no evidence shows that cervical ripening followed by delayed induction of labor reduces the rate of cesarean delivery.[23]

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Contributor Information and Disclosures
Author

Aaron E Goldberg, MD Assistant Professor, Department of Obstetrics and Gynecology, Virginia Commonwealth University Health System; Associate Director, US Special Operations Combat Medic Program, VCU Medical Center

Aaron E Goldberg, MD is a member of the following medical societies: Association of Professors of Gynecology and Obstetrics, Medical Society of Virginia, AAGL

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard S Legro, MD Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Pennsylvania State University College of Medicine; Consulting Staff, Milton S Hershey Medical Center

Richard S Legro, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society of Reproductive Surgeons, American Society for Reproductive Medicine, Endocrine Society, Phi Beta Kappa

Disclosure: Received honoraria from Korea National Institute of Health and National Institute of Health (Bethesda, MD) for speaking and teaching; Received honoraria from Greater Toronto Area Reproductive Medicine Society (Toronto, ON, CA) for speaking and teaching; Received honoraria from American College of Obstetrics and Gynecologists (Washington, DC) for speaking and teaching; Received honoraria from National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Thi.

Chief Editor

Carl V Smith, MD The Distinguished Chris J and Marie A Olson Chair of Obstetrics and Gynecology, Professor, Department of Obstetrics and Gynecology, Senior Associate Dean for Clinical Affairs, University of Nebraska Medical Center

Carl V Smith, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, Council of University Chairs of Obstetrics and Gynecology, Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Robert K Zurawin, MD Associate Professor, Chief, Section of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine

Robert K Zurawin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Society of Laparoendoscopic Surgeons, Texas Medical Association, AAGL, Harris County Medical Society, North American Society for Pediatric and Adolescent Gynecology

Disclosure: Received consulting fee from Ethicon for consulting; Received consulting fee from Bayer for consulting; Received consulting fee from Hologic for consulting.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Jodie Rai, MD, and James R Schreiber, MD, to the development and writing of this article.

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