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All patients hospitalized in 1982 at the Department of Gynecology in Malmö because of malignancy of the cervix uteri attended an interview study concerning the presence of cervical cancer among their nearest relatives. In addition, these patients were questioned concerning earlier gonorrheal infection. The blood group was determined as also was the secretory status and Gm allotype. As a control group the families of the male consorts were used. Cervical cancer was found significantly more often in mothers of the patients (7.9%) than in the consorts' mothers (1.0%). Sisters, aged 20 or over, of the patients had cervical cancer significantly more often (7.5%) than sisters of the consorts (1.1%). Moreover, cervical cancer in mothers and/or sisters was found in 15.6% of the patients. In cases of invasive cancer or previously operated CIS, this figure was 17.5%. The patients did not differ significantly from the normal population regarding blood group or secretory status. A somewhat lower, although non-significant, frequency of Gm(1) allotype was found in patients with invasive cancer, compared with patients with CIS. Patients with a positive family history of cancer had more often had gonorrhea (24%) than patients with a negative family history (18%). The study indicates a multifactorial etiology for cervical cancer.

A new gel-formulation for intracervical application of prostaglandin E2 (PGE2) has been prepared. As a vehicle for the gel a cross-link starch polymer is used. PGE2 substance is added to the starch polymer and after homogenization and lyophilization a PGE2 powder is obtained. The powder can be stored at room temperature for more than four months without inactivation of the prostaglandin. Before clinical application a few ml of saline is added to the powder giving, within 30 seconds, an easily-handled ready to use PGE2-gel. Chemical analysis by spectrophotometric technique reveals that the amount of unchanged PGE2 is the same in the new gel-formulation as in a conventional cellulose gel. In a randomized double-blind study the new PGE2-gel was intracervically applied to twenty nulliparae before abortion by dilatation and evacuation (D & E). Ten women were given a gel containing 0.25 mg PGE2 (PGE2-gel) and ten a gel without PGE2 (placebo gel). It was found that the PGE2-gel, in contrast to the placebo gel, produced a rapid ripening of the cervix facilitating the subsequent D & E. No adverse systemic or local reactions were found during or after the treatment.

A new gel delivery system for the local application of prostaglandin E2 consists of drug incorporated in the matrix of a cross-linked starch polymer. The properties of the starch powder provide a stabilizing milieu for the labile prostaglandin E2 and, by addition of saline, a ready-to-use gel for immediate local administration. The gel offers advantages over existing preparations in terms of chemical and microbiological stability, homogeneity, and dosage safety. This report outlines the pharmaceutical aspects involved in the development of the delivery system.

A single dose of 0.5 mg prostaglandin E2 in viscous gel was administered intracervically to induce labor in 150 patients with a favorable cervix. All but 5 patients (97 per cent) were delivered within 12 hours. No adverse maternal or fetal effects were registered. The method, which enables induction without primary amniotomy, was easy to perform and well accepted by the patients.

Mucus glycoproteins (mucins) were extracted from human cervical pregnancy mucus by 6 M-guanidinium chloride in the presence of proteinase inhibitors. Purification was subsequently achieved by isopycnic density-gradient centrifugation in CsCl/ guanidinium chloride gradients. The purified macromolecules represented approx. 85% of the total and were devoid of nucleic acids and proteins, as judged by analytical density-gradient centrifugation, disc electrophoresis and u.v. spectroscopy. Sedimentation-velocity centrifugation revealed a single unimodal peak with S20,W 50.1S in 0.2M-NaCl and 37.0S in 6 M-guanidinium chloride. Molecular weights obtained by light-scattering were 9.7 X 10(6) and 5.9 X 10(6) in 0.2M-NaCl and 6 M-guanidinium chloride respectively. The chemical analyses were typical of those of epithelial mucins. The macromolecules contained approx. 20% (w/w) of protein, and 65% (w/w) was accounted for as carbohydrate. Serine and threonine constituted 32 mol/100 mol and proline 10 mol/100 mol of the amino acids. The major sugars found were N-acetylglucosamine (12.8%), N-acetylgalactosamine (9.7%), galactose (18.7%), sialic acid (15.0%) and fucose (7.5%).

Proteoglycans were extracted from human uterine cervix with 4 M-guanidinium chloride in the presence of proteinase inhibitors. They were purified by density-gradient centrifugation in 4 M-guanidinium chloride/CsCl (starting density 1.32 g/ml) followed by DEAE-cellulose and Sepharose chromatography. Only one polydisperse proteoglycan was found. s020,w was 2.1S and the weight-average molecular weight was 73 000 (sedimentation-equilibrium centrifugation) to 110 500 (light-scattering). The core protein was monodisperse, with an apparent molecular weight of 47 000. The proteoglycan contained about 30% protein and probably two or three glycosaminoglycan side chains per molecule. High contents of aspartate, glutamate and leucine were found. The glycan moiety of the proteoglycan was exclusively dermatan sulphate, with a co-polymeric structure with approximately equal quantities of iduronic acid- and glucuronic acid-containing disaccharides.

A new gel for local application of prostaglandins has been elaborated. The new gel, based on a lyophilized prostaglandin E2 (PGE2) starch powder, seems to have solved most of the pharmaceutical and clinical problems associated with local administration of prostaglandins. In a randomized double-blind study, 50 nulliparous patients with an unfavorable cervical state at term were given 2 ml gel containing 0.5 mg PGE2 (PGE2 gel) or gel without PGE2 (placebo gel). The gel was deposited into the cervical canal. Among patients given PGE2 gel, 11 of 25 had induced labor, delivering without further stimulation within 24 hours. In patients given placebo gel, 2 of 25 were delivered with 24 hours. This difference is statistically significant (P less than .01). Patients undelivered after treatment with PGE2 gel achieved a considerable and statistically significant improvement of cervical score, whereas in patients in whom labor was not induced successfully by placebo gel treatment no significant changes in cervical score were registered. In a subsequent open study another 70 term patients of varied parity were given 0.5 mg PGE2 gel. Thirty-eight patients (54%) had successfully induced labor. Among the remaining undelivered patients, considerable ripening of the cervix occurred. Thus, the cervical score changed from a mean of 3.2 prior to treatment to a mean of 6.5 by 24 hours after treatment. Gastrointestinal discomforts were not observed. Signs of uterine hyperstimulation were registered in 1 patient.

Eight primigravid women with a mean gestational age of 9.4 weeks (9 to 10 weeks) who were admitted for first-trimester abortion by dilatation and evacuation were preoperatively treated for 6 hours with either intravenous infusion of oxytocin or a strictly intracervical application of prostaglandin E2 (PGE2) in viscous gel. Myometrial activity was monitored by intrauterine pressure recording throughout the treatment. Contractile activity was more pronounced in the oxytocin-treated group, whereas cervical priming occurred after the PGE2 treatment only. Intracervical PGE2-gel is suggested to have direct effects on the cervical tissues, independent of uterine contractile activity. Furthermore, myometrial stimulation induced by escape of gel into the extra-amniotic space can be avoided by adjusting the volume of gel and technique of application to the dimensions of the cervix.

One hundred nulliparas at term were randomly given oxytocin intravenously or prostaglandin E2 (PGE2) gel (0.5 mg PGE2) intracervically in order to study the effect on cervical ripening and the frequency of successful inductions. In the presence of a favorable cervix both methods seemed equally efficacious in inducing labor. However, when the cervix was unfavorable, 53% of the patients could be delivered with PGE2 gel, compared with 31% when oxytocin was given. In patients with a highly unfavorable cervix this difference was significant (P less than 0.02). In patients not induced into labor, PGE2 gel caused a considerable ripening of the cervix, with a change in Bishop score from 2.9 to 6.3. In patients undelivered after oxytocin stimulation, no change in Bishop score occurred. This effect of locally applied PGE2 gel on cervical ripening was highly significant (P less than 0.001). No adverse maternal or perinatal effects were observed, irrespective of the mode of treatment.

From 18 apparently healthy women wearing a copper-IUD, endometrial biopsy specimens were obtained under hysteroscopic control, both from the site of the IUD and from a distant area. The fibrinolytic activity proved significantly higher in the former specimens than in the latter. The results provide a theoretical basis for the development of an IUD which releases a synthetic inhibitor of fibrinolysis.

A single intracervical instillation of prostaglandin E2 (1.0 mg or 0.5 mg in viscous gel) was given to dilate the cervix before dilatation and evacuation in patients with missed abortion or intrauterine fetal death in late pregnancy. The 1.0-mg dose of PGE2 gave more prominent cervical dilatation in early pregnancy. In late pregnancy 1.0 mg PGE2 induced labor in the majority of patients and with shorter induction delivery time than in patients given 0.5 mg PGE2. There was no uterine hypertonus and no patients complained of gastrointestinal symptoms. We conclude that intracervical instillation of 1.0 mg of PGE2 in viscous gel is a safe and effective method both for dilating the cervix before dilatation and evacuation and as a method of inducing labor in patients with intrauterine fetal death.

In 54 patients with an unripe cervix in late third trimester, in which gestational age had been properly determined by repeated ultrasound scannings, labor was induced by intracervical application of 0.5 mg PGE2 in viscous gel. It was found that the outcome of the induced labor was not related to the gestational duration, but to the pre-inductive cervical score. Thus, the number of successful inductions was smaller and induction-delivery time longer, the lower the cervical score. Moreover, instrumental deliveries occurred most frequently in nulliparous women, with a low pre-inductive cervical score. Taking into consideration the difficulties of labor induction in the present type of patient, the overall proportion of instrumental deliveries (17%, including 7% cesarean sections) was low. No maternal or fetal side effects were observed. It is concluded that intracervical application a small dose of PGE2 in gel can be recommended for cervical priming and labor induction in pre- and post-term pregnancy.

The effect of the calcium antagonist nifedipine on premature labor was investigated in ten carefully selected patients. The main aim of treatment was to inhibit uterine activity and delivery for 3 days during which time fetal lung maturation was accelerated by glucocorticoid treatment. In all 10 patients, uterine activity was abolished during the 3 days of treatment and delivery was also postponed. No serious maternal side effects were observed. All children were delivered in good condition. All survived and were alive and well at 1 year.

A new PGE2-gel, based on a cross-linked starch powder, has been developed. This gel seems to have solved several of the pharmaceutical and practical problems connected with local administration of prostaglandins. In a three-center study 120 nulliparous patients were given 0.5 mg PGE2 in 2.2 ml gel intracervically prior to dilatation of the cervix and evacuation of the uterus in late first trimester. Considerable cervical dilatation was obtained within 15 h. The frequency of side effects, including pain and gastro-intestinal discomfort was low. The technique can be recommended for outpatients.

The effects of the calcium antagonist, nifedipine, on uterine activity induced by prostaglandins F2 alpha (PGF2 alpha) and E2 (PGE2) were studied in women undergoing therapeutic midtrimester abortion, and in patients with a missed abortion in the 16th to 27th week of pregnancy. In the five subjects receiving intra-amniotic PGF2 alpha (25 to 40 mg) for midtrimester abortion, nifedipine (30 mg orally) decreased uterine activity from a mean of 372 to 203 Montevideo Units. The effect on the intensity of the contractions was pronounced; frequently and basal tone were little affected. In patients with missed abortion, uterine contractions were induced by extra-amniotic application of PGE2 (0.5 to 1.5 mg) in a viscous gel. The activity was often more irregular than that in the women receiving intra-amniotic PGF2 alpha. However, nifedipine (30 mg orally) had a marked inhibitory effect on the uterine contractions. It is concluded that nifedipine can be used for treatment of uterine hyperactivity induced by prostaglandins. Combined treatment with beta 2-adrenoceptor stimulants might be considered.

High molecular weight glycopeptides and glycosaminoglycans were isolated from the human uterine cervix. The major part of the material (82%) was derived from cervical mucins. The remainder contained hyaluronic acid (3%), heparan sulphate (2%) and dermatan sulphate (13%). Chondroitin sulphate and keratan sulphate were not present, but chondroitin sulphate-like segments were included in the dermatan sulphate. The composition of the cervix apart from the mucus-filled crypts is similar to that of other fibrous connective tissues.

Prostaglandin E2 (PGE2) suspended in a viscous gel was deposited intracervically to 115 patients at term with an unripe cervix. 45 of these patients were given a single dose of 1.0 mg PGE2, whereas the remaining 70 received only half that dose, i.e. 0.5 mg. Irrespective of dose greater than 60 per cent of the patients were induced into labor and delivered without further stimulation within less than 24 hours. The mean induction delivery time was 10 hours. In the remaining patients a considerable ripening of the cervix was registered. Hypercontractility did occur in one patient given 1.0 mg PGE2, otherwise no maternal side effects were observed. There were no adverse effects on the fetuses. The number of instrumental deliveries was 19 per cent including 9 per cent cesarean sections. It is concluded that locally applied PGE2-gel can be used to produce ripening of the cervix and/or induce labor in patients at term with an unripe cervix. Since there was practically no difference in efficiency between the two doses but one case of hyperstimulation in patients given 1.0 mg PGE2, the smaller dose, i.e. 0.5 mg is recommended.

16 patients were treated with the fibrinolytic inhibitor tranexamic acid in an initial i.v. dose of 1 g followed by an oral dose of 4 g a day for one week and 3 g a day for two weeks. Biopsy specimens of superficial veins were obtained before and on the last day of treatment and examined histochemically for their fibrinolytic activity. Tranexamic acid did not suppress the fibrinolytic activity in the vessel walls, which is the most important link in the fibrinolytic defence system against thrombosis.

In a randomized double-blind study a viscous gel, containing 0.25 mg prostaglandin E2 (PGE2-gel) or without prostaglandin (placebo gel), was applied intracervically in twenty-two nulliparous patients just before termination of early pregnancy by dilatation and evacuation (D & E). Within twelve hours a marked ripening of the cervix was found in all the eleven patients receiving PGE2-gel. Thus, a significant change in cervical dilatation from mean 5.4 mm to mean 10.7 mm occurred. Furthermore, a considerable softening of the cervix was registered. In the eleven patients receiving placebo gel, no significant changes in cervical dilatation or consistency were found. The subsequent D & E was easily performed in all patients treated with PGE2-gel. However, in three of the patients given placebo gel, D & E was difficult to carry out because of an unfavorable cervical state. To eliminate or decrease myometrial activity the calcium antagonist nifedipine was given orally to eight patients at application and five hours after application of 0.25 mg PGE2-gel. None of the patients recognized uterine contractions. However, also in these patients significant changes in cervical consistency and dilatation occurred within twelve hours. No side effects of the treatment were observed. It is concluded, that a preoperative, intracervical single application of 0.25 mg PGE2 seems to be useful to ripen the unfavorable cervix before subsequent termination of early pregnancy by D & E.

To terminate pregnancy 15 women with an established diagnosis of missed abortion or intrauterine dead fetuses were treated with 1.0 mg Prostaglandin E 2 in viscous gel applied as a single intracervical dose. -- Abortion was induced after a mean of 7.0 hours in 8 patients with a mean gestational age of 15.0 weeks, and a subsequent evacuation of the uterine cavity was easily performed. -- Complete abortion/delivery was obtained in 7 patients with a gestational age of 33 weeks. The over-all mean induction/delivery time was 7.5 hours. -- Apart from pain related to uterine contractions no side effects were observed and no complications occurred. It is concluded that the present technique represents a promising alternative in the treatment of patients with missed abortion or intrauterine dead fetuses.

Fifty-four women with an unripe cervix at term were given 0.5 mg intracervical prostaglandin E2 (PGE2) gel. In 37 of them (70%) the cervix ripened within 5 h and seven of them were in labor at that time. Of the remaining 30 patients, 15 were randomly given an i.v. oxytocin infusion and 13 were delivered within 12 h. In 17 women (30%) the cervix was still unfavorable 5 h after PGE2-gel application but seven of them had a favorable cervix when reassessed 24 h after PGE2-gel instillation. All these patients went into labor with an i.v. infusion of oxytocin. The remaining 10 patients required another dose of PGE2-gel and subsequent i.v. oxytocin. Only in two of these patients did induction fail so that delivery by Caesarean sections was required. All infants were born in good condition.

A survey of connective tissue in general and human cervical connective in particular is presented. It is concluded that about 90% of the human cervix consists of fibrous connective tissue which, according to the composition of the collagen and the proteoglycans, is very similar to that in skin and sclera. The high activity of collagenase probably gives the cervical connective tissue from pregnant women its potential to ripen following prostaglandin treatment. Electron microscopical examination has revealed an increased amount of amorphous substance after such treatment. This may be caused partly by degraded collagen fibers and partly by newly synthesized proteoglycans.

Intracervical application of prostaglandin E2 in the late first trimester induces (1) softening of the cervix tissue; (2) increase in sulfated glycosaminoglycans (18 +/- 12%, mean +/- SEM); (3) no change in hyaluronic acid and water; (4) decrease in pepsin-extractable collagen, and (5) apparent decrease in collagenase. A high activity of collagenase in combination with a replacement of collagen with sulfated glycosaminoglycans may be of importance for the ripening process.

A new gel for intracervical application of prostaglandin E2 (PGE2) has been elaborated and evaluated. The main component of the gel is a cross-linked starch polymer to which prostaglandins can be added and preserved for long-term storage (> 12 months). In a double blind study, 20 patients requiring legal abortion in late first trimester were given gel containing 0.25 mg PGE2 or gel without PGE2. The gel was applied within the cervical canal. In all patients receiving PGE2-gel, a rapid ripening of the cervix occurred which facilitated the subsequent dilatation and evacuation. In patients receiving gel without PGE2 cervix did not ripen. In a subsequent open study, 30 patients were treated with PGE2-gel before therapeutic abortion. The same degree of cervical ripening was registered as for the patients receiving PGE2-gel in the double blind study. In 50 patients at term, intracervical application of 3 ml gel containing 0.05 mg PGE2 induced labor in 27 cases, i.e. 54 per cent of the patients. In the remaining undelivered women, a prominent cervical ripening occurred within 24 hours. No side effects of the treatment were observed. We conclude the new PGE2-gel to be a promising future alternative in the treatment of patients with an unfavorable cervix, prior to surgical evacuation of the uterus in late first trimester abortion, as well as before induction of labor at term.

In 7 primigravidae admitted for first trimester abortion by dilatation and evacuation, 0.5 mg PGE2 in viscous gel (5 patients) or placebo gel (2 patients) was applied intracervically 6 hours prior to the operation. Throughout the treatment period intrauterine pressure was recorded. Application of placebo gel induced no cervical ripening or myometrial activation. In all patients receiving active gel, a marked improvement of the cervical state was induced by the treatment. In three cases, this priming occurred in parallel to minimal changes in myometrial activity, without regular uterine contractions. In two patients, marked uterine activation was registered due to partly extraamniotic application. It is suggested, that the PGE2-gel has a direct effect on the cervical tissues. Further, the risk of partially applying the gel in the extraamniotic space, thus stimulating the myometrium, depends on the gel volume relative to the dimensions of the cervical canal and the application technique.

The methods used to date to ripen the unfavorable cervix during pregnancy have considerable disadvantages, chiefly from the practical point of view. Intracervical application of a small dose (0.5 mg) of prostaglandin E2 (PGE2) in viscous gel is a safe, easily performed and effective method to ripen the cervix in both early and late pregnancy. A new starch-based gel seems to have solved the pharmaceutical problems associated with gel preparations used hitherto. The histological and biochemical changes induced by local application of PGE2 are similar to those occurring spontaneously during late pregnancy.

In order to achieve ripening of the uterine cervix or induce labour in patients at term with an unfavourable cervical state, 1 mg of prostaglandin E2 (PGE2), suspended in a viscous gel, was instilled into the cervical canal. In a pilot study, 41 patients received the PGE2-gel. Twenty-three of these, (56%), went into labour, and delivery occurred without further stimulation within 15 hours. In the remaining 18 patients, there was a marked improvement of the cervical state, which changed from an average (modified) Bishop score of 2.5 to 6.1 within 24 hours. In a double-blind study comprising 20 nulliparae, 10 received gel containing PGE2 and 10 gel without prostaglandin. Cervical state did not change significantly (Bishop score 3.6 and 4.0) after 24 hours in patients receiving placebo gel. In those receiving PGE2 gel, 8 went into labour and were delivered without further induction within 13 hours. Two patients showed an increase in Bishop score from 3 to 6 and 7, respectively, after 24 hours. They were then induced by oxytocin and delivery occurred after 8 and 10 hours. The results suggest that administration of PGE2 intracervically can induce ripening of the cervix in patients at term with an unfavourable cervical state, and thus facilitate delivery.