Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen.

OBJECTIVE: To screen for bacterial vaginosis (BV) and to investigate the effect of treatment with vaginal clindamycin in order to observe the effect on late miscarriage and delivery prior to 37 completed weeks (primary outcome). DESIGN: Randomised consent design for clinical trials according to Zelen. SETTING: Southeast region of Sweden. POPULATION: A total of 9025 women were screened in early pregnancy. METHODS: A total of 819 women with a Nugent score of 6 and above were considered to have BV and treated according to Zelen allocation. The incidence of late miscarriage and spontaneous (noniatrogenic) preterm birth was assessed. MAIN OUTCOME MEASURES: Late miscarriage and spontaneous preterm delivery before 37 weeks. RESULTS: Therapy with vaginal clindamycin had no significant impact on the incidence of spontaneous preterm delivery prior to 37 completed weeks; OR 0.90, 95% CI 0.40-2.02 (primary outcome variable). However, only 1 of 11 women in the treatment group versus 5 of 12 in the control group delivered prior to 33 completed weeks; OR 0.14, 95% CI 0.02-0.95. Treatment was associated with 32 days longer gestation for the 23 participants who had late miscarriage or spontaneous preterm birth (P= 0.024, Mann-Whitney U test) and significantly fewer infants had a birthweight below 2,500 g (secondary outcome). A follow up of infants born preterm 4 years postnatally indicated that extending gestational age did not increase the number of sequelae. CONCLUSIONS: Clindamycin vaginal cream therapy was associated with significantly prolonged gestation and reduced cost of neonatal care in women with BV. Early screening for BV and treatment with clindamycin saved approximately 27 euro per woman.

Diagnosis of bacterial vaginosis: need for validation of microscopic image area used for scoring bacterial morphotypes.

BACKGROUND: The diagnosis of bacterial vaginosis (BV) is often made according to Nugent's classification, a scoring system based on bacterial counting of Gram stained slides of vaginal secretion. However as the image area of the microscope field will influence the number of morphotypes seen there is a need to standardise the area. METHODS: A graph intended for recalculation of number of bacterial morphotypes seen by the observer using 1000 x magnification from various microscope set-ups was constructed and applied to data sets typical for scoring BV. The graph was used in recalculation of Nugent scores, which were also compared with the Ison/Hay scores to evaluate the consequences for the diagnosis of BV. RESULTS: The observed image area differed by 300% among the investigated microscope set-ups. In two different data sets, one treatment study and one screening study, a considerable change in the number of women classified as intermediate was seen when the graph was used to standardise the image area. The recalculated numbers were also compared to the Ison/Hay classification. Weighted kappa indexes between the different methods were 0.84, 0.88, and 0.90, indicating that the methods are comparable. CONCLUSION: Because of the considerable differences among image areas covered by different microscope set-ups used in Nugent and Ison/Hay scoring, there is a need to standardise the area in order to reach comparable scores reflecting the diagnosis of BV in different laboratories. The differences in the intermediate group will have a considerable effect on the results from both treatment and prevalence studies, even though the kappa indexes indicate very good agreement between the methods used.

Treatment with 2% clindamycin vaginal cream prior to first trimester surgical abortion to reduce signs of postoperative infection: a prospective, double-blinded, placebo-controlled, multicenter study.

BACKGROUND: Bacterial vaginosis (BV) and intermediate flora is known risk-factor for postoperative infection after surgical termination of pregnancy. Vaginal application of 2% clindamycin cream is an efficacious treatment for BV, but it is not known whether preoperative administration of clindamycin cream might reduce the signs of post-abortion infection after surgical termination of pregnancy. AIM: To evaluate whether preoperative treatment with clindamycin cream might reduce the signs of post-abortion infection after legal abortion. DESIGN: Prospective, double-blinded, placebo-controlled, multicenter study. MATERIAL AND METHODS: Consecutive women attending for surgical termination prior to 11+4 gestational weeks were approached. We randomized participants to preoperative vaginal treatment with 2% clindamycin cream or placebo cream in a double-blinded fashion. At all visits vaginal smears were air dried on microscopy slides to be stored. The rate of postoperative pelvic infection according to our definition was the main outcome variable, the cure rates of BV and of intermediate flora were secondary outcome variables. RESULTS: Of 1655 enrolled women, 1102 were evaluable for analyses. Fifty-eight women developed signs of post-abortion infection. Preoperative treatment with clindamycin cream significantly (RR: 4.2, 95% C.I. 1.2-15.9) reduced the risk of post-abortion infection among women with abnormal vaginal flora (BV and intermediate flora). Treatment with clindamycin cream in women with normal lactobacilli flora did not demonstrate any difference compared to the non-treatment group. CONCLUSION: Preoperative treatment for at least three days with clindamycin cream significantly reduced the risk for developing signs of post-abortion infection only among women with preoperative abnormal vaginal flora (BV and intermediate flora).

The effects of estradiol on blood lipids and lipoproteins in postmenopausal women.

Endogenous sex steroids seem to exert a major influence on plasma lipoprotein levels. During menopause, endogenous estradiol (E2) levels decrease, and the low-density lipoprotein cholesterol concentration, which gradually increases with age, rises more rapidly, with mean plasma levels exceeding those of age-matched men. It is surprising that the reduction of endogenous E2 does not appear to influence high-density lipoprotein cholesterol levels. Women who experience early menopause have a higher incidence of coronary heart disease than do premenopausal women of similar age; however, this risk is decreased in women treated with oral estrogens. Oral administration of E2 increases plasma concentrations of estrone, E2, and high-density lipoprotein cholesterol, and decreases plasma concentrations of total and low-density lipoprotein cholesterol. This effect seems to be dose-dependent. Increased high-density lipoprotein (HDL) cholesterol concentration depends primarily on an HDL2 subfraction increase. It is interesting to speculate that the effects of oral estrogen replacement on plasma lipoproteins might be important in reducing coronary heart disease risk. Sequential addition of progestogens attenuates the effects of estrogen on plasma lipids and lipoproteins to some degree. However, the type and dose of the progestogen are important. Most progestogens derived from 19-nortestosterone, for example, reduce high-density lipoprotein cholesterol and, in higher doses, increase low-density lipoprotein cholesterol levels. In contrast, progestogens derived from 17-hydroxyprogesterone exert only minor effects on plasma lipoproteins. As with oral contraceptives, the net effect of estrogen-progestogen replacement therapy on plasma lipoproteins depends on the dose and potency of the involved drugs.

Plasma carnitine and renal-carnitine clearance during pregnancy.

This study assessed the time course of decrease in plasma carnitine during pregnancy and compared the renal clearance of carnitine during late pregnancy with nonpregnant women. As early as the 8th wk of pregnancy, the mean (+/- SD) value of total plasma-carnitine concentration in 19 women was significantly decreased from 39.0 +/- 6.3 to 32.8 +/- 4.6 mumol/l and the values continued to fall to 17.3 mumol/l by the 36th wk. The pattern was due to a fall in free-carnitine level; acylcarnitine remained unchanged. In 12 other women examined during late pregnancy, the renal clearance of acylcarnitine was significantly higher than in nonpregnant women, 53.9 +/- 29.4 versus 13.3 +/- 3.0 ml/min, in contrast to free carnitine, 3.5 +/- 2.8 versus 2.8 +/- 1.9 ml/min. Urinary excretion of carnitine (expressed per mol creatinine) did not differ between the two groups. Pregnant women showed sustained excretion of carnitine in the presence of low plasma-carnitine concentrations.

Lipoprotein changes during treatment of pelvic endometriosis with medroxyprogesterone acetate.

Ten women with endometriosis were treated with medroxyprogesterone acetate (MPA), 150 mg intramuscularly every second week. After 2 weeks, there was a significant (8%) decrease in the high-density lipoprotein (HDL) concentration. This reduction became more pronounced after 8 and 24 weeks' medication. The HDL reduction was confined to the HDL2 subfraction, which was decreased by 15%, 33%, and 58% after 2, 8, and 24 weeks, respectively; there was no significant change in the HDL3 concentration. During treatment, there was a continuous increase in the mean MPA plasma level and a strong inverse correlation between this level and the mean HDL and HDL2 cholesterol concentrations. It was concluded that MPA affects HDL metabolism in a dose-dependent way and in the same direction as other progestins.

Cholesterol esterification rate and its relation to lipoprotein levels in plasma in normal human pregnancy.

The lecithin:cholesterol acyl transfer (LCAT) reaction produces cholesteryl esters and lysolecithin in plasma. The rate of LCAT is related to the plasma lipoprotein concentrations. During pregnancy there are pronounced elevations of the lipid and lipoprotein concentrations. Therefore, we studied the LCAT rate and its relation to the lipid levels in plasma lipoproteins in 19 healthy women before conception, every sixth to eighth week during pregnancy, and 8 weeks after delivery. In the first part of gestation the mean molar LCAT rate (the amount of cholesteryl esters produced during a certain time, in micromoles per liter per hour) remained unchanged, whereas pronounced elevations were seen in the very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and HDL2 levels. The molar LCAT rate did not increase until the last trimester of pregnancy, when it reached a maximal 20% mean increase simultaneous with the maximal increase of the mean triglyceride and VLDL levels and a slight decline of the HDL2 elevation. The mean fractional LCAT rate (the part of unesterified cholesterol that is esterified during a certain time, in percent per hour) showed a continuous decrease from the fourteenth until the twenty-eighth week, simultaneous with a progressive rise of the mean cholesterol and low-density lipoprotein (LDL) concentrations. During pregnancy the molar LCAT rate was positively correlated to the VLDL concentration and negatively to the HDL2 level, and the fractional LCAT rate was negatively correlated to the LDL concentration.

Effects on the lipoprotein metabolism of an antiandrogen-estrogen oral contraceptive drug.

The effects on the lipoprotein metabolism of six cycles of treatment with 2 mg of the anti-androgenic progestogen Cyproterone acetate + 50 micrograms of ethinyl estradiol were prospectively studied in 22 healthy premenopausal women. The plasma level of cholesterol (C) was unchanged, while the levels of HDL-C and its subfractions HDL2-C and HDL3-C were significantly elevated after only one cycle. The LDL-C decreased after one month but then returned to pretreatment levels. VLDL-C was unchanged. The phospholipid concentrations within the various lipoprotein fractions generally resembled those of the corresponding cholesterol fraction. The levels of fibrinogen in plasma and of triglycerides in plasma and in the lipoprotein fractions were elevated. It is concluded that the drug had a predominant and rather pronounced estrogenic profile.

Plasma lipoproteins including high density lipoprotein subfractions during normal pregnancy.

In 19 healthy women the levels of plasma lipoprotein fractions were determined before conception, at exact gestational ages every six to 8 weeks during pregnancy, and eight weeks after delivery. The high density lipoprotein level was elevated in the 14th week and showed a maximum rise by 41% in the 28th week of pregnancy because of a doubling of the high density lipoprotein2 level. The low density lipoprotein level decreased in early pregnancy but then increased continuously. The very low density lipoprotein triglyceride concentration showed a continuous increase from week 14, and in week 36, it was three times higher than before pregnancy. During lactation, eight weeks after delivery, the low density lipoprotein concentration remained elevated, whereas the other lipoproteins had returned to prepregnancy levels.

Climacteric symptoms in an unselected sample of Swedish women.

A questionnaire on climacteric symptoms was sent to every woman living in the city of Linköping, Sweden (120,000 inhabitants) who was born in 1928 or 1930. Of the 1246 women concerned, 1118 (90%) responded. At the time of the survey, 252 women (23%) were pre-menopausal. In the total sample, 10% had undergone hysterectomy and/or bilateral oophorectomy. The median age at natural menopause was 51 yr. Climacteric symptoms were reported by 75% of the women, the predominating complaints being sweating attacks and hot flushes. Vaginal dryness and tenderness were experienced by 30% of the post-menopausal women, the discomfort tending to become more common as the duration of the post-menopausal period lengthened. After the menopause, every third women experienced periods of depression more often than previously. Depression was positively correlated to the severity of the vasomotor symptoms. Fifty percent of the women expressed interest in receiving oestrogen treatment, although only 7% were using oestrogens at the time of the survey. This discrepancy is probably due to widespread apprehension in Swedish society - shared by the doctors - in regard to 'hormonal treatment'.

Profound alterations of the lipoprotein metabolism during danazol treatment in premenopausal women.

Twelve women with pelvic endometriosis were treated with 600 mg of danazol daily for 24 weeks. The molar and fractional lecithin:cholesterol acyl transfer (LCAT) rates and the concentrations of cholesterol, phospholipids, and triglycerides were determined in plasma and in the very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and HDL2 and HDL3 fractions before, during, and after the medication. After 2 weeks the HDL, HDL2, and HDL3 cholesterol concentrations were reduced by 49%, 73%, and 29%, respectively, while the LDL level was increased by 14%. The molar and fractional LCAT rates decreased during treatment, and these reduced LCAT rates are consistent with a reduced fractional LDL removal. Within 8 weeks after cessation of medication, all parameters had returned to the pretreatment levels.

Plasma lipoproteins during and after danazol treatment.

Twelve women with pelvic endometriosis were treated with danazol, at a dose of 200 mg three times daily, over a 24-week period. The concentrations of cholesterol and triglycerides were determined in plasma and in the lipoprotein fractions. After only 2 weeks the mean high density lipoprotein (HDL) cholesterol had already decreased by 49% and 6 weeks later the reduction was 59%. The low density lipoprotein (LDL) cholesterol concentration increased by 14% after 2 weeks and by 34% after 8 weeks. The triglycerides increased by 20% after 2 weeks. Eight weeks after cessation of treatment the lipoprotein fractions had returned to the pretreatment levels.

L-norgestrel and progesterone have different influences on plasma lipoproteins.

Twenty-six postmenopausal women who had been on cutaneous oestradiol treatment for 3-6 months were given either 120 micrograms of 1-norgestrel (n = 13) or 300 mg of progesterone (n = 13) sequentially for another 6 months. The concentrations of cholesterol, phospholipids and triglycerides were determined in plasma and in the HDL, HDL2, HDL3, LDL and VLDL fractions before and after one, three and six cycles of progestin treatment. Already after 11 days on 1-norgestrel, the mean HDL cholesterol and the mean HDL phospholipid concentrations were reduced by 15%. The reduction of the HDL-lipids was mainly confined to the HDL2 fraction which was decreased by 25-30%. L-norgestrel also reduced the mean TG concentration both in the VLDL and the combined LDL + HDL fractions. Progesterone gave only minor changes of the plasma lipids and lipoproteins. Reduced HDL, especially HDL2, concentration, as induced by 1-norgestrel, might increase the risk for ischaemic heart disease. Therefore, it seems that, as regards the effects on the lipoproteins, progesterone might be more suitable than the 19-nortestosterone derivative 1-norgestrel for postmenopausal sequential hormonal therapy.

High density lipoprotein subfractions during oral and cutaneous administration of 17 beta-estradiol to menopausal women.

Thirty eight women with menopausal vasomotor symptoms were randomly allocated to 6 months treatment with either 2-4 mg micronized estradiol given orally or 3 mg estradiol applied cutaneously. The concentrations of cholesterol (C) and phospholipids (PL) were determined in high density lipoprotein (HDL) and its subfractions HDL2 and HDL3 twice before treatment and after 2, 4, and 6 months of medication. Oral estradiol increased the C and PL concentration in the HDL2 fraction in a dose-dependent way. With 2 mg estradiol orally the HDL3 fraction did not change, whereas 4 mg estradiol orally increased the C and PL concentrations in the HDL3 fraction. Cutaneous treatment with estradiol did not influence the lipid level in HDL or its subfractions. It is concluded that the rise of HDL during estrogen treatment is mainly caused by an elevation of the HDL2 fraction. Furthermore, the route of administration of estrogens has a profound influence on the metabolism of the HDL subfractions.

Lipoproteins during oral and cutaneous administration of oestradiol-17 beta to menopausal women.

Thirty-eight post-menopausal women were randomly allocated to substitution treatment with either oestradiol-17 beta orally (2-4 mg) or cutaneously (3 mg). The concentrations of cholesterol (C), triglycerides (TG) and phospholipids were determined in the high density lipoprotein (HDL)-, the low density lipoprotein (LDL)- and the very low density lipoprotein (VLDL)- fractions twice before medication and after 2, 4 and 6 months of treatment. Both treatments gave satisfactory clinical results. Oral doses increased the HDL and decreased the LDL thus raising the HDL-C/LDL-C ratio. The higher oral dose also increased the TG concentration. Cutaneous oestradiol gave only minimal changes of the lipoproteins. The lipoprotein changes observed during treatment with oral oestradiol might reduce the risk for atherosclerotic disease. Therefore, from a lipoprotein point of view, oral oestradiol treatment probably could be considered beneficial. The cutaneous oestradiol treatment had comparable clinical effects without any influence on the lipoprotein pattern.