Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial

Abstract

Objective To determine whether nitric oxide donors can induce cervical ripening before surgical Design Prospective, randomised controlled trial.Setting Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow.Participants Forty-eight primigravid women undergoing surgical termination of pregnancy before 12 weeks of gestation. MethodsThe women were randomised to receive per vaginam before surgery either the nitric oxide donor isosorbide mononitrate, the nitric oxide donor glyceryl trinitrate, the prostaglandin analogue gemeprost, or no treatment. Main outcome measuresThe cumulative force required to dilate the cervix to 8 mm was measured objectively and the cervical diameter before surgical dilatation was recorded.Results Following isosorbide mononitrate or gemeprost, a lower cumulative force was required to dilate the cervix to 8 mm and a higher cervical diameter before dilatation was recorded. Pretreatment with glyceryl trinitrate reduced the cumulative force required to dilate the cervix but had no effect on cervical diameter. ConclusionsLike the prostaglandin analogue gemeprost, the nitric oxide donors isosorbide mononitrate and glyceryl trinitrate can effect cervical ripening. Nitric oxide donors may provide an alternative to prostaglandins for cervical ripening before surgical procedures in the first trimester.termination of pregnancy in the first trimester. INTRODUCTIONThe control of cervical ripening is crucial to the process of human parturition. Animal studies have shown that nitric oxide, a free radical with a short half-life', is a fundamental mediator of the ripening process. The nitric oxide generating system is present in the rat cervix and is up-regulated during labour both at term and preterm2s. In pregnant guinea pigs the local application of the nitric oxide donor, sodium nitroprusside, effectively produces cervical ripening without inducing labour". Cervical ripening is an active process involving remodelling of the cervical tissue. This process can be induced pharmacologically in the first trimester to facilitate procedures such as surgical termination. Preoperative cervical ripening reduces the morbidity of surgical termination, including haemorrhage, incomplete uterine evacuation, uterine perforation and cervical trauma5-'. The role of nitric oxide in human cervical ripening has not been investigated. We hypothesise that nitric oxide donors can effect cervical ripening in humans. We therefore performed a randomised controlled trial to determine whether the nitric oxide donors, isosorbide mononitrate, and glyceryl trinitrate, can induce effective cervical ripening before surgical termination of pregnancy. In addition, we compared their ripening effects with those of the prostaglandin analogue gemeprost, the cervical priming agent currently used in our hospital. METHODSA prospective randomised controlled trial was performed involving 48 primigravid women referred for surgical termination of pregnancy by vacuum aspiration in the first trimester. The study was approved by the local res...

Inflammatory pathways in female reproductive health and disease

“…In the cervix, IL1B stimulates MMPs (Watari et al 1999), which is likely involved in the process of collagen breakdown during cervical ripening which occurs before and in the early phases of parturition (Yoshida et al 2002). Additionally, leukocytes invading the cervix release nitric oxide, which again induce cervical ripening (Thomson et al 1997, Ledingham et al 2000. A pathway by which inflammation induces parturition might involve initiation of inflammatory stimuli signalling via Toll-like receptors, which results in PG and MMP production in addition to leukocyte invasion into reproductive tissues, and culminating in myometrial contractility, rupture of membranes and cervical ripening (Challis et al 2009).…”

Effects of Progesterone on iNOS, COX-2, and Collagen Expression in the Cervix

“…Changes occurring in the cervix during the ripening process initially were thought to be passive; however, it is now known that the ripening process is an active process with the consistency of the cervix progressively changing (Danforth et al 1974;Ito et al 1979;Forman et al 1982a,b;Conrad and Ueland 1983;Uldbjerg et al 1983a-c;Leppert 1992;Leppert and Yu 1994). The mechanisms and mediators that control cervical ripening and parturition are still largely unknown even though nitric oxide (NO) and prostaglandins (PGs) have been shown to be involved in the ripening cascade and parturition (Stys et al 1981;Szalay et al 1981;Ekman et al 1983a-c,e;Calder and Greer 1992;Calder 1994;Buhimschi et al 1996;Ali et al 1997;Chwalisz et al 1997; Thomson et al 1997;Ledingham et al 2000).…”

“…Treatment with NO donors, such as isosorbidemononitrate and glyceryl-trinitrate in humans, stimulate the ripening process (Thomson et al 1997;Norman et al 1998; Thomson et al 1998). Inducible nitric oxide synthase (iNOS) is present in the cervix of many different species during pregnancy and increases during labor, suggesting a role for NO in the ripening process and parturition (Nathan 1992;Gilbert and Herschman 1993a,b;Kitajima et al 1994;Vane et al 1994;Buhimschi et al 1996;Ali et al 1997;Ledingham et al 2000).…”

“…Inducible nitric oxide synthase (iNOS) is present in the cervix of many different species during pregnancy and increases during labor, suggesting a role for NO in the ripening process and parturition (Nathan 1992;Gilbert and Herschman 1993a,b;Kitajima et al 1994;Vane et al 1994;Buhimschi et al 1996;Ali et al 1997;Ledingham et al 2000). Local applications of NO in animals and humans produce characteristics associated with the ripening process ; Thomson et al 1997; Thomson et al 1998;Shi et al 2000b). N-nitro-L-arginine methyl ester, a nonspecific NOS inhibitor, prolongs time cervical dilation and decreases cervical extensibility.…”

Serum profile of isosorbide mononitrate after vaginal administration in the third trimester

“…These tablets are formulated for oral administration, but we have previously found them to be effective when administered vaginally for cervical ripening in the first trimester 1 .…”