Introduction

In pregnancy, the uterine cervix serves 2 major functions. First, it maintains its firmness (ie, physical integrity) 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 dilatation, labor, and delivery of a fetus.

Uterine Characteristics

The human uterus is composed of 2 basic parts, the fundus and the cervix. The fundus is composed of myometrium, predominantly smooth muscle cells, and the endometrium. The endometrium 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. 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.

Cervical ripening

Cervical ripening usually begins prior to the onset of labor contractions and is necessary for cervical dilatation and the passage of the fetus. Cervical ripening is the result of a series of complex biochemical processes that ends with rearrangement and realignment of the collagen molecules. The cervix thins, softens, relaxes, and opens in response to uterine contractions, which pull the cervix over the presenting fetal part.

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, which leads to reduced bridging among the collagen fibers and, thus, a 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), which leads to collagen fiber separation. All of these changes cause cervical softening (ie, ripening). With uterine contractions, the ripened cervix dilatates, 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 dilatates 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 dilatation 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, and dilatation resulting from these processes plus uterine contractions. This is a complicated series of events in which many things occur both simultaneously and sequentially. Research in this area is complex because studying human subjects is difficult and many differences exist between species.

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, which leads 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:

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, which leads 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.

For physicians to stop preterm labor successfully, it has been proposed that they must halt both uterine contractions and cervical ripening. 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.

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 dilatation, 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.

Bishop score is calculated as follows:

Ultrasound assessment of the cervix helps measure the length of the cervix and helps determine the absence or presence of cervical funneling. A 2000 study by Cook and Ellwood (based on 120 at-risk women) demonstrated with linear regression analysis that prior to 20 weeks of pregnancy, a cervical length of less than 21 mm is highly predictive of preterm labor and delivery.

Detection of fetal fibronectin in cervicovaginal secretions has also recently been used. Fetal fibronectin is a glycoprotein found in amniotic fluid and at the chorionic decidual interface. The presence of this protein in cervicovaginal secretions predicts preterm labor; its absence 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.

Induction of cervical ripening

Bishop scores are somewhat subjective, but a score of 5 or less suggests further ripening is needed, while a score of 9 or greater suggests that 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.

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.

Prostaglandin E1 analog (misoprostol) use was described recently 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 several studies to be quite effective in inducing cervical ripening and labor. The application of the medication can be repeated every 4 hours.

Misoprostol has also been administered orally (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 major risk of the above 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 with a dinoprostone insert is safe, and this significantly shortens induction-to-delivery times.

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. 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 a very effective antiprogesterone and antiglucocorticoid that works by binding to progesterone and glucocorticoid receptors. Randomized trials have shown it to be very effective in inducing labor. However, these same studies show it to have no effect on the cervix or on cervical ripening.

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.

Balloon catheter

A 30- to 50-mL Foley catheter filled with saline is effective in inducing cervical ripening and dilatation. 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 (Mullin et al), the catheter is combined with a saline solution as an extraamniotic infusion. A possible problem with an extraamniotic saline infusion is that it may be associated with a greater risk of chorioamnionitis than other methods of labor induction. Prospective trials have shown that insertion of a Foley catheter is at least as effective as PGE2 gels, perhaps even more effective. This is particularly true in nulliparous women.

Hygroscopic dilatators

Several products are available that can be placed in the cervix and dilatated by water absorption. Laminaria are made from dried seaweed. Commercial products, Dilapan and Lamisil, are produced from synthetic hygroscopic material. Several dilatators 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 dilatators 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 dilatators unless they have a specific indication such as mitral valve prolapse or positive genital beta- Streptococcus infection.

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.

Summary of induction of cervical ripening

Economic burden of mistimed cervical ripening

Preterm labor and delivery

Accurate dating of pregnancy using early prenatal care and ultrasound is advised before cervical ripening and induction of labor. Mistimed cervical ripening and induction can result in unplanned preterm birth.

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 at less than 32 weeks of gestation showed significant language difficulties. In 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 of 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.

Economic and other consequences of postterm delivery

Postdate labor induction in a woman with an unripe cervix is also associated with difficulties. Labor is longer, more materials are used, and the rate of cesarean deliveries is higher. For example, the rate of cesarean deliveries in nulliparous women who are electively induced for postdate pregnancy is twice that of nulliparous women with the onset of spontaneous labor. The doubling of the rate leads to increased morbidity for the patient and increased cost to the health care delivery system. Therefore, whenever possible, cervical ripening is advised before induction in postdate pregnancies in which the cervix is unripe.

Contraindications to cervical ripening

Contraindications to cervical ripening include all contraindications to induction of labor. Contraindications also include ruptured membranes, regular contractions, and maternal fever.