Fertility and obstetric outcomes after curettage versus expectant management in randomised and non-randomised women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage.

OBJECTIVE: To assess fertility and obstetric outcomes in women treated with curettage or undergoing expectant management for an incomplete miscarriage after misoprostol treatment. STUDY DESIGN: Between June 2012 and July 2014, we conducted a multicentre randomised clinical trial (RCT) with a parallel cohort study for non-randomised women, treated according to their preference. In the RCT 30 women were allocated curettage and 29 expectant management. In the cohort 197 women participated; 65 underwent curettage and 132 women underwent expectant management. Primary outcome was curation, defined as either an empty uterus on sonography at six weeks or an uneventful clinical follow-up. We used questionnaires to assess fertility and obstetric outcome of the first new pregnancy subsequent to study enrolment. RESULTS: Curation was seen in 91/95 women treated with curettage (95.8%) versus 134/161 women managed expectantly (83.2%) (p=0.003). The response rate was 211/255 (82%). In 198 women pursuing a new pregnancy, conception rates were 92% (67/73) in the curettage group versus 96% (120/125) in the expectant management group (OR 0.96, 95% CI 0.89;1.03, p=0.34), with ongoing pregnancy rates of 87% (58/67) versus 78% (94/120), respectively (OR 1.12, 95% CI 0.99;1.28, p=0.226). Preterm birth rates were 1/46 in the curettage group versus 8/81 in the expectant management group (OR 0.22, 95% CI 0.03;1.71 P=0.15). Caesarean section rates were 23% and 24% for women in the curettage group and expectant management group respectively. CONCLUSION: In women with an incomplete evacuation of the uterus after misoprostol treatment, curettage and expectant management does not lead to different fertility and pregnancy outcomes, as compared to expectant management.

Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison.

STUDY QUESTION: What is the treatment success rate of systemic methotrexate (MTX) compared with expectant management in women with an ectopic pregnancy or a pregnancy of unknown location (PUL) with low and plateauing serum hCG concentrations? SUMMARY ANSWER: In women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations, expectant management is an alternative to medical treatment with single-dose systemic MTX. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: MTX is often used in asymptomatic women with an ectopic pregnancy or a PUL with low and plateauing serum hCG concentrations. These pregnancies may be self-limiting and watchful waiting is suggested as an alternative, but evidence from RCTs is lacking. The results of this RCT show that expectant management is an alternative to treatment with systemic MTX in a single-dose regimen in these women. STUDY DESIGN, SIZE, DURATION: A multicentre RCT women were assigned to systemic MTX (single dose) treatment or expectant management, using a web-based randomization program, block randomization with stratification for hospital and serum hCG concentration (<1000 versus 1000-2000 IU/l). The primary outcome measure was an uneventful decline of serum hCG to an undetectable level (<2 IU/l) by the initial intervention strategy. Secondary outcome measures included additional treatment, side effects and serum hCG clearance time. PARTICIPANTS, SETTING, METHODS: From April 2007 to January 2012, we performed a multicentre study in The Netherlands. All haemodynamically stable women >18 years old with both an ectopic pregnancy visible on transvaginal sonography and a plateauing serum hCG concentration <1500 IU/l or with a PUL and a plateauing serum hCG concentration <2000 IU/l were eligible for the trial. MAIN RESULTS: We included 73 women of whom 41 were allocated to single-dose MTX and 32 to expectant management. There was no difference in primary treatment success rate of single-dose MTX versus expectant management, 31/41 (76%) and 19/32 (59%), respectively [relative risk (RR) 1.3 95% confidence interval (CI) 0.9-1.8]. In nine women (22%), additional MTX injections were needed, compared with nine women (28%) in whom systemic MTX was administered after initial expectant management (RR 0.8; 95% CI 0.4-1.7). One woman (2%) from the MTX group underwent surgery compared with four women (13%) in the expectant management group (RR 0.2; 95% CI 0.02-1.7), all after experiencing abdominal pain within the first week of follow-up. In the MTX group, nine women reported side effects versus none in the expectant management group. No serious adverse events were reported. Single-dose systemic MTX does not have a larger treatment effect compared with expectant management in women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations. WIDER IMPLICATIONS OF THE FINDINGS: Sixty percent of women after expectant management had an uneventful clinical course with steadily declining serum hCG levels without any intervention, which means that MTX, a potentially harmful drug, can be withheld in these women. BIAS, LIMITATION AND GENERALISABILITY: A limitation of this RCT is that it was an open (not placebo controlled) trial. Nevertheless, introduction of bias was probably limited by the strict criteria to be fulfilled for treatment with MTX. STUDY FUNDING: This trial is supported by a grant of the Netherlands Organization for Health Research and Development (ZonMw Clinical fellow grant 90700154). TRIAL REGISTRATION: ISRCTN 48210491.

[The practice guideline 'Vaginal discharge' (first revision) from the Dutch College of General Practitioners; a response from the perspective of gynaecology]. / De standaard 'Fluor vaginalis' (eerste herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de gynaecologie.

The Dutch College of General Practitioners (NHG) revised their practice guideline on vaginal discharge. From a gynaecological point of view, relocation of cervix problems from this guideline to the NHG guideline 'The STD consultation' is not practical. Moreover, the role of simple, but effective diagnosis with a microscope in the primary-care setting cannot be overemphasized. The reluctance to oral treatment is rather inopportune, because once-only ingestion has the advantage of promoting compliance. As physical examination is not always necessary in a recurrent Candida infection, treatment performed by the patient with imidazole compounds is a possibility that does not always result in abuse or increased resistance.

Epidemiology of neonatal group B streptococcal disease in the Netherlands before and after introduction of guidelines for prevention.

OBJECTIVES: (1) To describe the epidemiology of neonatal group B streptococcal (GBS) disease over five years (1997-2001) in the Netherlands, stratified for proven and probable sepsis and for very early (<12 h), late early (12 h - <7 days) and late (7-90 days) onset sepsis. (2) To evaluate the effect of the introduction in January 1999 of guidelines for prevention of early onset GBS disease based on risk factors. METHODS: Data on cases were collected in collaboration with the Dutch Paediatric Surveillance Unit and corrected for under-reporting by the capture-recapture technique. RESULTS: Total incidence of proven very early onset, late early onset and late onset GBS sepsis was 0.32, 0.11 and 0.14 per 1000 live births, respectively, and of probable very early onset, late early onset and late onset GBS sepsis was 1.10, 0.18 and 0.02 per 1000 live births, respectively. Maternal risk factors were absent in 46% of the proven early onset cases. Considerably more infants with proven GBS sepsis were boys. 64% of the infants with proven very early onset GBS sepsis were first born compared with 47% in the general population. After the introduction of guidelines the incidence of proven early onset sepsis decreased considerably from 0.54 per 1000 live births in 1997-8 to 0.36 per 1000 live births in 1999-2001. However, there was no decrease in the incidence of meningitis and the case fatality rate in the first week of life. The incidence of late onset sepsis also remained unchanged. CONCLUSION: After the introduction prevention guidelines based on risk factors there has been a limited decrease in the incidence of proven early onset GBS sepsis in the Netherlands. This study therefore recommends changing the Dutch GBS prevention guidelines.

Using a new HPV detection system in epidemiological research: change of views on cervical dyskaryosis?

UNLABELLED: The prevalence of human papillomavirus (HPV) rises with increasing histological severity of neoplasia, more cigarettes smoked per day and higher lifetime number of sexual partners in women with cervical dyskaryosis. Recently, the highly sensitive SPF10 primers and Inno-LiPA (line probe assay) HPV prototype research assay became available for the detection and typing of HPV. BACKGROUND: using this system, we challenged the previously reported findings. STUDY DESIGN: the study group comprised 304 women referred because of abnormal pap smears in whom a histological diagnosis was made. Data on the lifetime number of sexual partners and smoking behaviour were obtained by questionnaire. HPV analysis was performed on cervical scrapes obtained at the enrollment visit. RESULTS: oncogenic HPV was found in 288 (95%) women. A total of 86 (30%) out of these 288 women disclosed multiple types. HPV 16 occurred significantly less often in multiple infections than was expected on the basis of chance alone. The grade of neoplasia was significantly associated with the presence of oncogenic HPV, and this association depended on the presence of HPV type 16. No association was found between grade of neoplasia and the presence of multiple HPV types. Neither the lifetime number of sexual partners nor smoking were associated with oncogenic HPV, the five most frequent HPV types separately or the presence of multiple types. CONCLUSION: we conclude that the association between the detection of HPV and the epidemiological risk factors, as found with the GP5/6 PCR in the past, could not be confirmed when using SPF10 PCR primers and LiPA HPV genotyping. We suggest that the number of sexual partners and smoking may be determinants of high HPV viral load rather than determinants of the presence of HPV per se.

No association of anti-Chlamydia trachomatis antibodies and severity of cervical neoplasia.

OBJECTIVE: To explore whether the presence of Chlamydia trachomatis antibodies is associated with the severity of neoplastic lesions in women with cervical dyskaryosis. METHODS: In a cross sectional study in two groups of women referred for an abnormal Papanicolaou smear (group A: 296, group B: 331 women) blood samples were analysed for antichlamydial antibodies by enzyme immunoassay. Cervical neoplasia was graded histologically. RESULTS: In group A no association was found between increasing grade of CIN and the presence of antichlamydial antibodies. The proportion (93%) of women with antichlamydial antibodies was higher in 14 women with (micro)invasive carcinoma than in women with CIN (35%). As the high prevalence of antichlamydial antibodies in women with cervical carcinoma is not consistent with prevalences reported in recent literature, we analysed a second group of women in which indeed the high prevalence was not confirmed CONCLUSION: Our results suggest that the presence of circulating antichlamydial antibodies is not associated with the severity of neoplastic lesions and it seems unlikely that C trachomatis has a role in the progression of cervical neoplasia.

Liberal diagnosis and treatment of intrauterine infection reduces early-onset neonatal group B streptococcal infection but not sepsis by other pathogens.

OBJECTIVE: Comparison of the incidence and case fatality of early-onset group B streptococcus sepsis and sepsis caused by other pathogens in neonates after change of management of intrauterine infection. METHODS: All infants delivered from 1988 through 1997 at a gestational age > or = 24 weeks with a birth weight > or = 500 gram without lethal congenital abnormalities were eligible for inclusion. Infants delivered by cesarean section before the onset of labor or rupture of membranes were excluded. During the first period (1988-1991) intrauterine infection was diagnosed by a temperature > 38 degrees C, during the second period (1992-1997) this diagnosis was made at a lower temperature (> or = 37.8 degrees C) or by fetal tachycardia > or = 160/min. Treatment of intrauterine infection was similar during both periods with 3 x 2 gram amoxicillin and 1 x 240 mg gentamicin every 24 hours intravenously during labor. Prophylactic treatment during labor was only given to women with a history of an earlier infant with early-onset group B streptococcus sepsis. RESULTS: During the first period 6,103 infants were included, during the second period 8,504. Intrauterine infection was diagnosed and treated more often in the second period (7.1% vs. 2.6%). The incidence of early-onset group B streptococcus sepsis was significantly lower in the second period than in the first period [0.2% vs. 0.4%; OR 0.5 (0.3-0.9)] and survival without disability higher [80% vs. 52%; OR 4.5 (1.4-16.5)]. However, in both periods the overall incidence of neonatal sepsis (3.6% vs. 3.5%) and overall mortality because of sepsis (14.3% vs.13.1%) were similar. CONCLUSIONS: Although the early detection of clinical signs of intrauterine infection might have been effective for the prevention of serious sequelae of early-onset group B streptococcus sepsis the overall incidence and mortality from neonatal sepsis remained unchanged. Evaluation of preventive measures for early-onset group B streptococcus sepsis should always take the incidence of neonatal sepsis caused by other pathogens into account.

Semmelweis: the combat against puerperal fever.

Groups A and B streptococci are of great significance in the history of obstetrics. Group A streptococci were a great threat to the puerperium, especially in the 19th century, when homebirth was replaced by institutional birth in lying-in hospitals. The history of the rise and fall of puerperal fever is indeed a tragedy. Some people, like Semmelweis, who brought new and important evidence based findings were not believed by their fellow obstetricians, an attitude that spoiled thousands of innocent lives. Even today group A streptococci, though seldom, may be the cause of puerperal sepsis. Group B streptococci are widespread and may cause sepsis and important lifelong morbidity or mortality of the newborn. Obstetricians today try to establish cost-effective prophylactic measures during labor to prevent these neonatal infections.

Risk indicators for neonatal early-onset GBS-related disease. A case-control study.

Risk indicators play an important role in the active prevention of neonatal Early-Onset GBS-related Disease (EOD). We studied the associations between potential risk indicators and the occurrence of EOD by means of a case-control study. All cases of EOD delivered in the Academic Medical Centre in Amsterdam between January 1988 and December 1995 were included. For each case we selected 3 controls, matched for date and time of birth. The association between continuous risk indicators and the occurrence of EOD was assessed using spline functions. Multivariable logistic regression analysis was performed to determine which risk indicators contributed independently. Forty-one cases were compared with 123 controls. In the multivariable analysis, gestational age < 37 weeks and intrapartum temperature > or = 37.4 degrees C showed to be statistically significant risk indicators for EOD, with odds ratios of 2.5 per week gestation and 1.6 per 0.1 degree C, respectively. After cesarean section the risk of EOD was significantly decreased (OR 0.13). Of the other potential risk indicators only prelabor rupture of membranes showed an increased risk, although the association was not statistically significant. Prolonged duration of ruptured membranes had no additional merit. Risk indicators that should be taken into account in strategies to prevent EOD are increased maternal temperature and decreased gestational age.

Neonatal early onset group B streptococcal infection. A nine-year retrospective study in a tertiary care hospital.

Retrospectively, morbidity and mortality of neonatal early onset group B streptococcal (GBS) infection were established. Risk factors and prognostic factors were determined. Between 1985 and 1993, 78 patients with early onset GBS disease were identified. The overall mortality rate was 23%. In 60 of 73 cases (82%) at least one of the investigated risk factors was present. Low birth weight was not an independent risk factor. Outcome of 44 of 60 survivors (73%) at the age of at least one year was obtained. Almost 30% of them had sequelae. The most important were spastic disorders and delayed psychomotor development. In 42% of patients with symptoms of GBS-infection within six hours after birth sequelae occurred. There were no sequelae among patients with symptoms after 6 hours. All 9 severely brain damaged infants showed symptoms shortly after birth. Mortality and adverse outcome rate were higher in infants with low gestational age or low 5 minute Apgar scores. Early treatment resulted in less mortality, but not in less sequelae. GBS-sepsis still causes significant mortality and leaves a substantial number of survivors damaged. Alertness to GBS-infection, even in the absence of risk factors, remains crucial for early treatment and good outcome.

Prevention of neonatal septicaemia due to group B streptococci.

Group B streptococcus is the leading cause of neonatal septicaemia. Major risk factors for early-onset disease are heavy maternal GBS colonization preterm delivery (and related low birthweight), preterm rupture of membranes, prelabour rupture of membranes, intrapartum fever, GBS urinary infection and low levels of maternal serum anti-GBS antibodies. Screening for maternal GBS colonization, a part of most current preventive strategies, can be targeted on all pregnant women or only on those with recognizable risk factors, and can be implemented antepartum or intrapartum. A culture in a selective broth is the 'gold standard' for detection of GBS colonization. The lower vagina (introitus) is the most suitable site for culturing, with the optional addition of an anorectal sample. The sensitivity of the available rapid GBS antigen tests for vagina samples seems too low to advocate their general use. Intrapartum prophylaxis with ampicillin, preferably targeted on GBS-colonized parturients with risk factors is, at present, the only strategy with established efficacy and safety to prevent early-onset infection. Vaginal chlorhexidine disinfection during labour in all women may, in addition offer a minor contribution to prevention. Late-onset GBS disease is unlikely to be reduced by these strategies. In the future, immunoprophylaxis may well prove to be the most safe and efficacious alternative to prevent GBS septicaemia, irrespective of age of onset, although protection of (very) preterm infants is unlikely.

Randomized study of vaginal chlorhexidine disinfection during labor to prevent vertical transmission of group B streptococci.

OBJECTIVE: To evaluate the effect of vaginal disinfection with chlorhexidine gel during labor on vertical transmission of group B streptococcus, as a method to prevent vertical transmission and subsequent neonatal early onset group B streptococcal disease. STUDY DESIGN: A prospective study with randomization of 1020 parturients to one of three groups as soon as labor started. In all parturients, anus, introitus and cervix were cultured semiquantitatively. Two groups were treated double-blindly with 10 ml of either a 0.3% chlorhexidine gel or a placebo gel, applicated around the portio and into the fornices. If labor still continued, a second application was given after 10 h. The third group received no treatment. Ear, pharynx and umbilicus of all newborns were also cultured semiquantitatively. RESULTS: Nine hundred and eighty one women were evaluated. The overall incidence of group B streptococcal carriership was 19.4%. Vertical transmission was 52.4% in the chlorhexidine group, 71.4% in the placebo group and 66.7% in the control group (P = 0.069). When testing the transmission rates for the chlorhexidine versus the combined placebo plus control group (69.3%), the difference was 16.9% (P = 0.026). CONCLUSION: Vaginal disinfection with a chlorhexidine gel during labor modestly reduces group B streptococcal vertical transmission. Because the method is cheap, simple and safe, it should be considered for routine use. Our results indicate that it may reduce the incidence of early onset group B streptococcal sepsis by 2-32%.

Significance of Gram's stain in rapid intrapartum screening for maternal carriership of group B streptococcus.

OBJECTIVE: Group B streptococcus (GBS, Streptococcus agalactiae) is an important cause of neonatal sepsis. Prevention is possible by intrapartum screening for maternal GBS carriership and antimicrobial treatment of colonized women with risk factors during labor. The conflicting results of diagnostic performance are reported both for the newly developed rapid GBS antigen tests and Gram's stain. METHODS: The value of Gram's stain in GBS screening was investigated prospectively in 1,020 women. Intrapartum Gram's stains of the cervix from these women and of the introitus from 510 of them were compared with cultures of the cervix, introitus, and anorectum in a semiquantitative way. RESULTS: The sensitivities of the cervical and introital Gram's stains were 25% and 31%, respectively, and the specificities 99% and 98%, respectively. Higher sensitivities (52% and 44%, respectively) were found in heavily colonized parturients. No significant influence of rupture of the membranes was detected. There was a poor correlation between the number of gram-positive cocci in the Gram's stain and the growth density. CONCLUSIONS: We do not recommend the routine use of the Gram's stain for intrapartum GBS detection because of both the limited sensitivity and positive predictive value.

Sensitivity of intrapartum group B streptococcal screening and in vitro comparison of four rapid antigen tests.

OBJECTIVES: To evaluate the sensitivity of intrapartum screening for group B streptococcal (GBS) colonization and to compare 4 rapid GBS antigen tests in vitro. DESIGN: Two swabs of the lower vagina of 769 parturients were taken; one swab was cultured, the other was frozen at -70 degrees C until antigen testing with the Group B Strep Test (Quidel) of the culture positive samples was performed. The Quidel test was then compared with 3 other rapid GBS antigen tests in vitro: Wellcogen Strep B (Wellcome Diagnostics), Slidex méningite Strepto B (bioMérieux) and ICON Strep B (Hybritech). The supernatant of 29 GBS cultures in Todd-Hewitt broth was tested in bacterial concentrations of 10(6), 10(7), and 10(8) Colony-forming Units (CFU)/ml, respectively. RESULTS: Lower vagina GBS carrier rate was 13.4% (103/769) and heavy colonization (growth density 3 and 4 on blood agar plates) was found in 5.2% (40/769). The Group B Strep Test detected 11% (11/103) of GBS carriers, with a sensitivity for heavy colonization of 25% (10/40). In vitro none of the tests scored positively with a concentration of 10(6) CFU/ml, while with 10(7) CFU/ml the enzyme immunoassay tests (Quidel, Hybritech) were more sensitive (McNemar test, P < 0.05) than the latex agglutination tests (Wellcome Diagnostics, bioMérieux). CONCLUSIONS: Although in vitro the enzyme immunoassay tests are more sensitive than the latex agglutination tests, sensitivity in vivo is too low to recommend the use of rapid antigen tests for general screening.