Antibiotics for prelabour rupture of membranes at or near term.

BACKGROUND: Prelabour rupture of the membranes (PROM) at or near term (defined in this review as 36 weeks' gestation or beyond) increases the risk of infection for the woman and her baby. The routine use of antibiotics for women at the time of term PROM may reduce this risk. However, due to increasing problems with bacterial resistance and the risk of maternal anaphylaxis with antibiotic use, it is important to assess the evidence addressing risks and benefits in order to ensure judicious use of antibiotics. This review was undertaken to assess the balance of risks and benefits to the mother and infant of antibiotic prophylaxis for PROM at or near term. OBJECTIVES: To assess the effects of antibiotics administered prophylactically to women with PROM at 36 weeks' gestation or beyond, on maternal, fetal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014). SELECTION CRITERIA: All randomised trials that compared outcomes for women and infants when antibiotics were administered prophylactically for prelabour rupture of the membranes at or near term, with outcomes for controls (placebo or no antibiotic). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed risk of bias in the included studies. Additional data were received from the investigators of included studies. MAIN RESULTS: This update includes an additional two studies involving 1801 women, giving a total of four included studies of 2639 women. Whereas the previous version of this review showed a statistically significant reduction in endometritis with the use of antibiotics, no such effect was shown in this update (average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.05 to 2.31). No differences were shown on the primary outcome measures of probable early-onset neonatal sepsis (average RR 0.69, 95%; CI 0.21 to 2.33); definite early-onset neonatal sepsis (average RR 0.57, 95% CI 0.08 to 4.26); maternal infectious morbidity (chorioamnionitis and/or endometritis) (average RR 0.48, 95% CI 0.20 to 1.15); stillbirth (RR 3.00, 95% CI 0.61 to 14.82); and perinatal mortality (RR 1.98, 95% CI 0.60 to 6.55), though the number of cases in the control group for these outcomes was low. There were no cases of neonatal mortality or serious maternal outcome in the studies assessed. Caesarean section was increased with the use of antibiotics (RR 1.33, 95% CI 1.09 to 1.61) as was duration of maternal stay in hospital (mean difference (MD) 0.06 days, 95% CI 0.01 to 0.11), largely owing to one study of 1640 women where repeat caesarean section, increased baseline hypertension and pre-eclampsia were evident in the antibiotic group, despite random allocation and allocation concealment.Subgroup analyses by timing of induction (early induction versus late induction) showed no difference in either probable or definite early-onset neonatal sepsis in the early induction group (RR 1.47, 95% CI 0.80 to 2.70 and RR 1.29, 95% CI 0.48 to 3.44, respectively) or the late induction group (RR 0.14, 95% CI 0.02 to 1.13 and RR 0.16, 95% CI 0.02 to 1.34, respectively), although there were trends toward reduced probable and definite early-onset neonatal sepsis in the late induction group. A test for subgroup differences confirmed a differential effect of the intervention on probable early-onset neonatal sepsis between the subgroups (Chi² = 4.50, df = 1 (P = 0.03), I² = 77.8%). No difference in maternal infectious morbidity (chorioamnionitis and/or endometritis) was found in either subgroup, though again there was a trend towards reduced maternal infectious morbidly in the late induction group (average RR 0.34, 95% CI 0.08 to 1.47). No differences were shown in stillbirth or perinatal mortality. The quality of the evidence for the primary outcomes using GRADE was judged to be low to very low. AUTHORS' CONCLUSIONS: This updated review demonstrates no convincing evidence of benefit for mothers or neonates from the routine use of antibiotics for PROM at or near term. We are unable to adequately assess the risk of short- and long-term harms from the use of antibiotics due to the unavailability of data. Given the unmeasured potential adverse effects of antibiotic use, the potential for the development of resistant organisms, and the low risk of maternal infection in the control group, the routine use of antibiotics for PROM at or near term in the absence of confirmed maternal infection should be avoided.

Calcium channel blockers for inhibiting preterm labour and birth.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in low- and middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 November 2013). SELECTION CRITERIA: All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different. MAIN RESULTS: This update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias.Two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.Comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (MD -5.40 days,95% CI -10.84 to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI -8.17 to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.No differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower-dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity. AUTHORS' CONCLUSIONS: Calcium channel blockers (mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longer-term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs.

Antenatal perineal massage for reducing perineal trauma.

BACKGROUND: Perineal trauma following vaginal birth can be associated with significant short-term and long-term morbidity. Antenatal perineal massage has been proposed as one method of decreasing the incidence of perineal trauma. OBJECTIVES: To assess the effect of antenatal digital perineal massage on the incidence of perineal trauma at birth and subsequent morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (22 October 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 10), PubMed (1966 to October 2012), EMBASE (1980 to October 2012) and reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials evaluating any described method of antenatal digital perineal massage undertaken for at least the last four weeks of pregnancy. DATA COLLECTION AND ANALYSIS: Both review authors independently applied the selection criteria, extracted data from the included studies and assessed study quality. We contacted study authors for additional information. MAIN RESULTS: We included four trials (2497 women) comparing digital perineal massage with control. All were of good quality. Antenatal digital perineal massage was associated with an overall reduction in the incidence of trauma requiring suturing (four trials, 2480 women, risk ratio (RR) 0.91 (95% confidence interval (CI) 0.86 to 0.96), number needed to treat to benefit (NNTB) 15 (10 to 36)) and women practicing perineal massage were less likely to have an episiotomy (four trials, 2480 women, RR 0.84 (95% CI 0.74 to 0.95), NNTB 21 (12 to 75)). These findings were significant for women without previous vaginal birth only. No differences were seen in the incidence of first- or second-degree perineal tears or third-/fourth-degree perineal trauma. Only women who have previously birthed vaginally reported a statistically significant reduction in the incidence of pain at three months postpartum (one trial, 376 women, RR 0.45 (95% CI 0.24 to 0.87) NNTB 13 (7 to 60)). No significant differences were observed in the incidence of instrumental deliveries, sexual satisfaction, or incontinence of urine, faeces or flatus for any women who practised perineal massage compared with those who did not massage. AUTHORS' CONCLUSIONS: Antenatal digital perineal massage reduces the likelihood of perineal trauma (mainly episiotomies) and the reporting of ongoing perineal pain, and is generally well accepted by women. As such, women should be made aware of the likely benefit of perineal massage and provided with information on how to massage.

Prophylactic antibiotics for inhibiting preterm labour with intact membranes.

BACKGROUND: The aetiology of preterm birth is complex and there is evidence that subclinical genital tract infection influences preterm labour in some women but the role of prophylactic antibiotic treatment in the management of preterm labour is controversial. Since rupture of the membranes is an important factor in the progression of preterm labour, it is important to see if the routine administration of antibiotics confers any benefit or causes harm, prior to membrane rupture. OBJECTIVES: To assess the effects of prophylactic antibiotics administered to women in preterm labour with intact membranes, on maternal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013). SELECTION CRITERIA: Randomised trials that compared antibiotic treatment with placebo or no treatment for women in preterm labour (between 20 and 36 weeks' gestation) with intact membranes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, and undertook quality assessment and data extraction. We contacted study authors for additional information. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with their respective 95% confidence intervals (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) was calculated where appropriate. MAIN RESULTS: In this update (2013), with the addition of three trials (305 women), the large ORACLE II 2001 trial continues to dominate the results of this review. This review now includes a total of 14 studies randomising 7837 women. No significant difference was shown in perinatal or infant mortality for infants of women allocated to any prophylactic antibiotics compared with no antibiotics. However, an increase in neonatal deaths was shown for infants of women receiving any prophylactic antibiotics when compared with placebo (RR 1.57, 95% CI 1.03 to 2.40; NNTH 149, 95% CI 2500 to 61). No reduction in preterm birth or other clinically important short-term outcomes for the infant were shown.Long-term child outcomes to seven years of age were available for infants in the UK enrolled in the ORACLE II trial. Comparing any antibiotics with placebo, a marginally non-statistically significant increase was shown in any functional impairment (RR 1.10, 95% CI 0.99 to 1.23) and cerebral palsy (CP) (RR 1.82, 95% CI 0.99 to 3.34). In subgroup analysis, CP was statistically significantly increased for infants of women allocated to macrolide and beta-lactam antibiotics combined compared with placebo (RR 2.83, 95% CI 1.02 to 7.88; NNTH 35, 95% CI 333 to 9).Further, exposure to any macrolide antibiotics (including erythromycin alone or erythromycin plus co-amoxiclav) versus no macrolide antibiotics (including placebo and co-amoxiclav alone) was shown to increase neonatal death (RR 1.52, 95% CI 1.05 to 2.19; NNTH 139, 95% CI 1429 to 61), any functional impairment (RR 1.11, 95% CI 1.01 to 1.20; NNTH 24, 95% CI 263 to 13) and CP (RR 1.90, 95% CI 1.20 to 3.01; NNTH 64, 95% CI 286 to 29). Exposure to any beta-lactam (beta-lactam alone or in combination with macrolide antibiotics) versus no beta-lactam antibiotics resulted in more neonatal deaths (RR 1.51, 95% CI 1.06 to 2.15; NNTH 143, 95% CI 1250 to 63) and CP (RR 1.67, 95% CI 1.06 to 2.61; NNTH 79, 95% CI 909 to 33), however no difference was shown in functional impairment.Maternal infection was reduced with the use of any prophylactic antibiotics compared with placebo (RR 0.74, 95% CI 0.63 to 0.86; NNTB 34, 95% CI 24 to 63) and any beta-lactam compared with no beta-lactam antibiotics (RR 0.80, 95% CI 0.69 to 0.92; NNTB 47, 95% CI 31 to 119). However, caution should be exercised with this finding due to the possibility of bias shown by funnel plot asymmetry. Any beta-lactam compared with no beta-lactam antibiotics was associated with an increase in maternal adverse drug reaction (RR 1.61, 95% CI 1.02 to 2.54; NNTH 17, 95% CI 526 to 7). AUTHORS' CONCLUSIONS: This review did not demonstrate any benefit in important neonatal outcomes with the use of prophylactic antibiotics for women in preterm labour with intact membranes, although maternal infection may be reduced. Of concern, is the finding of short- and longer-term harm for children of mothers exposed to antibiotics. The evidence supports not giving antibiotics routinely to women in preterm labour with intact membranes in the absence of overt signs of infection.Further research is required to develop sensitive markers of subclinical infection for women in preterm labour with intact membranes, as this is a group that might benefit from future novel interventions, including new modalities of antibiotic therapy. The results of this review demonstrate the need for future trials in the area of preterm birth to include assessment of long-term neurodevelopmental outcome.

A self-adjuvanting multiepitope immunogen that induces a broadly cross-reactive antibody to hepatitis C virus.

UNLABELLED: We describe a peptide-based strategy for HCV vaccine design that addresses the problem of variability in hypervariable region 1 (HVR1). Peptides representing antibody epitopes of HVR1 from genotype 1a were synthesized and incorporated into multideterminant immunogens that also included lipid moieties and helper T (T(h)) cell epitopes. Mice inoculated with these polyepitopes generated strong antibody responses. Antibody titers were highest in mice inoculated with polyepitope immunogens which contained the lipid moiety dipalmitoyl-S-glyceryl cysteine (Pam2Cys). Antisera were tested for their potential to neutralize HCV by 3 currently available assays. Antibodies elicited in mice by the polyepitope-based vaccine candidates were able to (1) bind to E2 expressed on the surface of E1/E2-transfected human embryonic kidney (HEK) 293T cells, (2) capture HCV of different genotypes (1, 2, and 3) from the serum of chronically infected humans in an immune capture RT-PCR assay and (3) inhibit HCVpp entry into Huh7 cells. Antibody present in the sera of patients chronically infected with HCV genotypes 1, 2, 3, and 4 also bound to the HVR1-based polyepitope. CONCLUSION: These results demonstrate the potential of self-adjuvanting epitope-based constructs in the development and delivery of cross-reactive immunogens that incorporate potential neutralizing epitopes present within the viral envelope of HCV.