Risk of obstetric anal sphincter injuries (OASIS) and anal incontinence: A meta-analysis.

BACKGROUND: Obstetric anal sphincter injuries (OASIS) are the commonest cause of anal incontinence in women of reproductive age. We determined the risk of anal sphincter defects diagnosed by ultrasound, and the risk of anal incontinence in (i) all women who deliver vaginally, (ii) in women without clinical suspicion of OASIS, and (iii) after primary repair of sphincter injury, by systematic review. METHODS: We searched major databases until June 2018, without language restrictions. Random effects meta-analysis was used to obtain pooled estimates of ultrasound diagnosed OASIS and risk of anal incontinence symptoms at various time points after delivery, and of persistent sphincter defects after primary repair. We reported the association between ultrasound diagnosed OASIS and anal incontinence symptoms using relative risk (RR) with 95 % CI. RESULTS: We included 103 studies involving 16,110 women. Of all women who delivered vaginally, OASIS were diagnosed on ultrasound in 26 % (95 %CI, 21-30, I2 = 91 %), and 19 % experienced anal incontinence (95 %CI, 14-25, I2 = 92 %). In women without clinical suspicion of OASIS (n = 3688), sphincter defects were observed in 13 % (10-17, I2 = 89 %) and anal incontinence experienced by 14 % (95 % CI: 6-24, I2 = 95 %). Following primary repair of OASIS, 55 % (46-63, I2 = 98 %) of 7549 women had persistent sphincter defect with 38 % experiencing anal incontinence (33-43, I2 = 92 %). There was a significant association between ultrasound diagnosed OASIS and anal incontinence (RR 3.74, 2.17-6.45, I2 = 98 %). INTERPRETATION: Women and clinicians should be aware of the high risk for sphincter defects following vaginal delivery even when clinically unsuspected. This underlines the need of careful and systematic perineal assessment after birth to mitigate the risk of missing OASIS. We also noted a high rate of persistent defects and symptoms following primary repair of OASIS. This dictates the need for provision of robust training for clinicians to achieve proficiency and sustain competency in repairing OASIS.

Risks of stillbirth and neonatal death with advancing gestation at term: A systematic review and meta-analysis of cohort studies of 15 million pregnancies.

BACKGROUND: Despite advances in healthcare, stillbirth rates remain relatively unchanged. We conducted a systematic review to quantify the risks of stillbirth and neonatal death at term (from 37 weeks gestation) according to gestational age. METHODS AND FINDINGS: We searched the major electronic databases Medline, Embase, and Google Scholar (January 1990-October 2018) without language restrictions. We included cohort studies on term pregnancies that provided estimates of stillbirths or neonatal deaths by gestation week. We estimated the additional weekly risk of stillbirth in term pregnancies that continued versus delivered at various gestational ages. We compared week-specific neonatal mortality rates by gestational age at delivery. We used mixed-effects logistic regression models with random intercepts, and computed risk ratios (RRs), odds ratios (ORs), and 95% confidence intervals (CIs). Thirteen studies (15 million pregnancies, 17,830 stillbirths) were included. All studies were from high-income countries. Four studies provided the risks of stillbirth in mothers of White and Black race, 2 in mothers of White and Asian race, 5 in mothers of White race only, and 2 in mothers of Black race only. The prospective risk of stillbirth increased with gestational age from 0.11 per 1,000 pregnancies at 37 weeks (95% CI 0.07 to 0.15) to 3.18 per 1,000 at 42 weeks (95% CI 1.84 to 4.35). Neonatal mortality increased when pregnancies continued beyond 41 weeks; the risk increased significantly for deliveries at 42 versus 41 weeks gestation (RR 1.87, 95% CI 1.07 to 2.86, p = 0.012). One additional stillbirth occurred for every 1,449 (95% CI 1,237 to 1,747) pregnancies that advanced from 40 to 41 weeks. Limitations include variations in the definition of low-risk pregnancy, the wide time span of the studies, the use of registry-based data, and potential confounders affecting the outcome. CONCLUSIONS: Our findings suggest there is a significant additional risk of stillbirth, with no corresponding reduction in neonatal mortality, when term pregnancies continue to 41 weeks compared to delivery at 40 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015013785.

Maternal and perinatal mortality and complications associated with caesarean section in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Universal and timely access to a caesarean section is a key requirement for safe childbirth. We identified the burden of maternal and perinatal mortality and morbidity, and the risk factors following caesarean sections in low-income and middle-income countries (LMICs). METHODS: For this systematic review and meta-analysis, we searched electronic databases including MEDLINE and Embase (from Jan 1, 1990, to Nov 20, 2017), without language restrictions, for studies on maternal or perinatal outcomes following caesarean sections in LMICs. We excluded studies in high-income countries, those involving non-pregnant women, case reports, and studies published before 1990. Two reviewers undertook the study selection, quality assessment, and data extraction independently. The main outcome being assessed was prevalence of maternal mortality in women undergoing caesarean sections in LMICs. We used a random effects model to synthesise the rate data, and reported the association between risk factors and outcomes using odds ratios with 95% CIs. The study protocol has been registered with PROSPERO, number CRD42015029191. FINDINGS: We included 196 studies from 67 LMICs. The risk of maternal death in women who had a caesarean section (116 studies, 2 933 457 caesarean sections) was 7·6 per 1000 procedures (95% CI 6·6-8·6, τ2=0·81); the highest burden was in sub-Saharan Africa (10·9 per 1000; 9·5-12·5, τ2=0·81). A quarter of all women who died in LMICs (72 studies, 27 651 deaths) had undergone a caesarean section (23·8%, 95% CI 21·0-26·7; τ2=0·62). INTERPRETATION: Maternal deaths and perinatal deaths following caesarean sections are disproportionately high in LMICs. The timing and urgency of caesarean section pose major risks. FUNDING: Ammalife Charity and ELLY Appeal, Barts Charity, and the UK National Institute for Health Research.

Type of obstetric anesthesia administered and complications in women with preeclampsia in low- and middle-income countries: A systematic review.

BACKGROUND: Delivery is often expedited with cesarean section, necessitating anesthesia, to prevent complications in women with preeclampsia. Anesthesia-associated risks in these women from low- and middle-income countries (LMICs) are not known. METHODS: We searched major databases (until February 2017) for studies on general vs. regional anesthesia in women with preeclampsia. We summarized the association between outcomes and type of anesthesia using a random effects model and reported as odds ratio (OR) with 95% confidence intervals (95% CIs). FINDINGS: We included 14 studies (10,411 pregnancies). General anesthesia was associated with an increase in the odds of maternal death sevenfold (OR 7.70, 95% CI 1.9 to 31.0, I2 = 58%) than regional anesthesia. The odds of pulmonary edema (OR 5.16, 95% CI 2.5 to 10.4, I2 = 0%), maternal intensive care unit admissions (OR 16.25, 95% CI 9.0 to 29.5, I2 = 65%), and perinatal death (OR 3.01, 95% CI 1.4 to 6.5, I2 = 56%) were increased with general vs. regional anesthesia. CONCLUSION: General anesthesia is associated with increased complications in women with preeclampsia undergoing cesarean section in LMIC.

External validation of preexisting first trimester preeclampsia prediction models.

OBJECTIVE: To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. STUDY DESIGN: A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. RESULTS: Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. CONCLUSION: There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care.

Short Communication: Maraviroc Once-Daily: Experience in Routine Clinical Practice.

To assess the efficacy and safety of maraviroc (MVC) administered once-daily in routine clinical practice. A retrospective multicenter study (27 centers in Spain) was conducted. Data were collected from the records of patients starting a regimen with MVC. Laboratory and clinical data were recorded every 3 months the first year and every 6 months thereafter. Data are presented as median and interquartile range. Among 667 patients treated with MVC, 142 (21.3%) received MVC once-daily: 108 (76.1%), 150 mg and 34 (23.9%), and 300 mg. Age was 47 (42-45) years, there were 76.1% men, and 81 (57%) patients had baseline HIV-RNA <50 copies/mL. Viral tropism was R5 in 118 (83.1%) patients. Reasons for prescribing MVC: salvage therapy (36.6%), drug toxicity (31.2%), simplification (16.9%), and immunodiscordant response (7.1%). Median follow-up was 13 (9-16) months. In 95.8%, a PI/r was part of the regimen (67% on dual therapy). At months 12 and 24, 73.3% and 68.2% of patients had HIV-RNA <50 copies/mL, respectively (p = .041 and p < .001 vs. baseline). CD4+ cell count increased by a median of 52 (-36,135) and 84 (-9.5,180) cells/mm3 at 12 and 24 months, respectively (p < .001 and p = .039 vs. baseline). Twenty-five (17.6%) patients discontinued MVC: virologic failure (6), medical decision (5), and other reasons (14). Two patients presented grade 3 adverse events (hypertransaminasemia, hypertriglyceridemia) without the need for MVC withdrawal, whereas MVC was discontinued in two patients due to gastrointestinal toxicity. In routine clinical practice, MVC once-daily combined with at least PI/r was virologically effective and well tolerated in a high percentage of pretreated patients.

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538.

Predictive value of vrk 1 and 2 for rectal adenocarcinoma response to neoadjuvant chemoradiation therapy: a retrospective observational cohort study.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by surgical resection is the standard therapy for locally advanced rectal cancer. However, tumor response following NACRT varies, ranging from pathologic complete response to disease progression. We evaluated the kinases VRK1 and VRK2, which are known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis, and as such are potential predictors of tumor response and may aid in identifying patients who could benefit from NACRT. METHODS: Sixty-seven pretreatment biopsies were examined for VRK1 and VRK2 expression using tissue microarrays. VRK1 and VRK2 Histoscores were combined by linear addition, resulting in a new variable designated as "composite score", and the statistical significance of this variable was assessed by univariate and multivariate logistic regression. The Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC) analysis were carried out to evaluate calibration and discrimination, respectively. A nomogram was also developed. RESULTS: Univariate logistic regression showed that tumor size as well as composite score were statistically significant. Both variables remained significant in the multivariate analysis, obtaining an OR for tumor size of 0.65 (95 % CI, 0.45-0.94; p = 0.021) and composite score of 1.24 (95 % CI, 1.07-1.48; p = 0.005). Hosmer-Lemeshow test showed an adequate model calibration (p = 0.630) and good discrimination was also achieved, AUC 0.79 (95 % CI, 0.68-0.90). CONCLUSIONS: This study provides novel data on the role of VRK1 and VRK2 in predicting tumor response to NACRT, and we propose a model with high predictive ability which could have a substantial impact on clinical management of locally advanced rectal cancer.

Anaesthesia-related maternal mortality in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: The risk factors contributing to maternal mortality from anaesthesia in low-income and middle-income countries and the burden of the problem have not been comprehensively studied up to now. We aimed to obtain precise estimates of anaesthesia-attributed deaths in pregnant women exposed to anaesthesia and to identify the factors linked to adverse outcomes in pregnant women exposed to anaesthesia in low-income and middle-income countries. METHODS: In this systematic review and meta-analysis, we searched major electronic databases from inception until Oct 1, 2015, for studies reporting risks of maternal death from anaesthesia in low-income and middle-income countries. Studies were included if they assessed maternal and perinatal outcomes in pregnant women exposed to anaesthesia for an obstetric procedure in countries categorised as low-income or middle-income by the World Bank. We excluded studies in high-income countries, those involving non-pregnant women, case reports, and studies published before 1990 to ensure that the estimates reflect the current burden of the condition. Two independent reviewers undertook quality assessment and data extraction. We computed odds ratios for risk factors and anaesthesia-related complications, and pooled them using a random effects model. This study is registered with PROSPERO, number CRD42015015805. FINDINGS: 44 studies (632,556 pregnancies) reported risks of death from anaesthesia in women who had an obstetric surgical procedure; 95 (32,149,636 pregnancies and 36,144 deaths) provided rates of anaesthesia-attributed deaths as a proportion of maternal deaths. The risk of death from anaesthesia in women undergoing obstetric procedures was 1·2 per 1000 women undergoing obstetric procedures (95% CI 0·8-1·7, I(2)=83%). Anaesthesia accounted for 2·8% (2·4-3·4, I(2)=75%) of all maternal deaths, 3·5% (2·9-4·3, I(2)=79%) of direct maternal deaths (ie, those that resulted from obstetric complications), and 13·8% (9·0-20·7, I(2)=84%) of deaths after caesarean section. Exposure to general anaesthesia increased the odds of maternal (odds ratio [OR] 3·3, 95% CI 1·2-9·0, I(2)=58%), and perinatal deaths (2·3, 1·2-4·1, I(2)=73%) compared with neuraxial anaesthesia. The rate of any maternal death was 9·8 per 1000 anaesthetics (5·2-15·7, I(2)=92%) when managed by non-physician anaesthetists compared with 5·2 per 1000 (0·9-12·6, I(2)=95%) when managed by physician anaesthetists. INTERPRETATION: The current international priority on strengthening health systems should address the risk factors such as general anaesthesia and rural setting for improving anaesthetic care in pregnant women. FUNDING: Ammalife Charity and ELLY Appeal, Bart's Charity.

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis.

BACKGROUND: Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs. METHODS: We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Review's protocol is CRD42014007547. FINDINGS: Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2,837,325 pregnancies). Women with epilepsy versus those without (2,809,984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02-2·32; I(2)=67%), antepartum haemorrhage (1·49, 1·01-2·20; I(2)=37%), post-partum haemorrhage (1·29, 1·13-1·49; I(2)=41%), hypertensive disorders (1·37, 1·21-1·55; I(2)=23%), induction of labour (1·67, 1·31-2·11; I(2)=64%), caesarean section (1·40, 1·23-1·58; I(2)=66%), any preterm birth (<37 weeks of gestation; 1·16, 1·01-1·34; I(2)=64%), and fetal growth restriction (1·26, 1·20-1·33; I(2)=1%). The odds of early preterm birth, gestational diabetes, fetal death or stillbirth, perinatal death, or admission to neonatal intensive care unit did not differ between women with epilepsy and those without the disorder. INTERPRETATION: A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy. FUNDING: EBM CONNECT Collaboration.

The efficacy and safety of maraviroc addition to a stable antiretroviral regimen in subjects with suppressed plasma HIV-RNA is not influenced by age.

There are few data about the immunovirological efficacy, safety/tolerability, and durability of maraviroc (MVC) addition to aging patients on suppressive antiretroviral therapy (cART) and undetectable viral load (<50 copies/ml). The aging population is underrepresented in most HIV clinical trials. This study included 80 patients aged ≥50 years and 161 aged <50 years and showed that after 48 weeks of treatment, there was no between-group differences in the median increase of CD4(+) T cells or the virological suppression rate. Safety and tolerability were also comparable. In multivariable analysis, the effect of age was not modified and was independent of the response to MVC. An immunological recovery of ≥100 CD4(+) T cells was significantly less common in those with a longer HIV history (≥15 years) (OR 0.43; p=0.016) or having <200/mm(3) CD4(+) T cells at MVC initiation (OR 0.27; p=0.004). Meanwhile, achieving a CD4/CD8 ratio ≥0.5 at week 48 was less likely in those with CD4(+) T cell counts <200 at MVC initiation (OR 0.09; p<0.0001) or with a previous AIDS event (OR 0.43; p=0.028). In summary, the immunovirological efficacy, safety/tolerability, and durability of MVC addition in patients virologically suppressed were independent of the patient's age at treatment onset.