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 (COX-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 also is involved in the process via its ability to stimulate an increase in glycosaminoglycans.

Cervical ripening is associated with increased activity of metalloproteinases, 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 also has 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 (bNOS) 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.

dEVALUATION 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 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 include ultrasound assessment of the cervix and detection of fetal fibronectin in cervicovaginal secretions.

Ultrasound assessment of the cervix helps measure the length of the cervix and helps determine the absence or presence of cervical funneling. A cervical length of less than 21 mm is highly predictive of preterm labor and delivery.

Detection of fetal fibronectin in cervicovaginal secretions also has been used recently. 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 also is predictive of response to prostaglandin application to the cervix at term in order to induce cervical ripening and labor.

dINDUCTION OF CERVICAL RIPENING

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/Cerviprime, 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. Note that Cytotec is classified as a pregnancy category X drug, and the manufacturer strongly opposes this off-label use of the medication.

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. 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 that can be given. Indeed, if no pressing indication for delivery exists and 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.

dAntiprogesterone

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.

dRelaxin

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 currently is not 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.

dBalloon 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 then is 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. Prospective trials have shown that insertion of a Foley catheter is at least as effective as PGE2 gels, perhaps more so. This particularly is true in nulliparous women.

dHygroscopic 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 Lamisil, 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 they have a specific indication such as mitral valve prolapse or positive genital beta-Streptococcus infection.

dMembrane 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 postulate certainly is consistent with the known stimulation of cervical ripening by prostaglandins.

dSummary 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 dilate the cervix effectively. The amount of uterine work to dilate a ripe cervix is thought to be approximately 1600 mm Hg, while the work to dilate an unripe cervix is estimated to be greater than 5 times that, or 10,000 mm Hg.

dEconomic and other consequence of postterm delivery

Postdate labor induction in a woman with an unripe cervix also is 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.