Methodius G. Tuuli

First-trimester assessment of placenta function and the prediction of preeclampsia and intrauterine growth restriction

Preeclampsia and intrauterine growth restriction (IUGR) are major contributors to perinatal mortality and morbidity worldwide. Both are characterized by impaired trophoblastic invasion of the maternal spiral arteries and their conversion from narrow muscular vessels to wide non‐muscular channels. Despite improvement in the understanding of the pathophysiology of these conditions, ability to accurately identify pregnant woman who will develop them is limited. This greatly impairs the development and testing of preventive interventions. While different measures of placental dysfunction have been associated with increased risk for adverse pregnancy outcomes, the ability of any single one to accurately predict these outcomes is poor. Developing predictive tests is further challenged by difficulty in the timing of the measurements, as both the structural and biochemical characteristics of the placenta change with increasing gestational age. The ideal screening test would accurately predict the development of adverse pregnancy outcomes early enough to provide a window for preventive interventions. Improvement in ultrasound technology provides potentially useful novel tools for evaluating placental structure, but measuresments need to be standardized in order to be useful. Maternal serum analyte screening is a noninvasive test of placental biochemical function, but present serum marker alone is not sufficiently accurate to suggest its routine use in clinical practice. The use of first trimester biochemical markers in combination with uterine artery Doppler screening is promising as a potential screening tool. Prospective longitudinal studies using standardized methodology are necessary to further evaluate the choice of parameters and strategies of combination to achieve the best predictive models. Copyright

Staples compared with subcuticular suture for skin closure after cesarean delivery: a systematic review and meta-analysis.

OBJECTIVE: To estimate whether staples or subcuticular suture closure is associated with a higher risk of wound complications when used for transverse skin incisions after cesarean delivery. DATA SOURCES: A systematic review and meta-analysis were performed through electronic database searches (MEDLINE, Cochrane, and Trial Registries). METHODS OF STUDY SELECTION: We searched electronic databases from 1966 to September 2010 for randomized controlled trials (RCTs) and prospective cohort studies comparing staples to subcuticular sutures after cesarean delivery. The primary outcome was occurrence of a wound complication (infection or separation). Secondary outcomes were components of the composite outcome, operating time, postoperative pain, cosmesis, and patient satisfaction. Heterogeneity was assessed using the &khgr;2 test for heterogeneity, and I2 test. Pooled odds ratios (ORs) were calculated using a fixed-effects model. We assessed publication bias using funnel plots and Egger test. RESULTS: Six studies met inclusion criteria: five RCTs and one prospective cohort study. Staple closure (n=803) was associated with a twofold higher risk of wound infection or separation compared with subcuticular suture closure (n=684) (13.4% versus 6.6%, pooled OR 2.06, 95% confidence interval [CI] 1.43–2.98). The number needed to harm associated with staple closure was 16. The increased risk persisted when analysis was limited to the RCTs (OR 2.43, 95% CI 1.47–4.02). There was no evidence of significant statistical heterogeneity among studies (&khgr;2=0.74, P=.327, I2=13.7%) or publication bias (Egger test, t=−0.86, P=.439). Staple closure was associated with shorter duration of surgery, whereas the two techniques appeared equivalent overall with regard to pain, cosmesis, and patient satisfaction. CONCLUSION: Staple closure is faster to perform but associated with a higher risk of wound complications.

Placental volume and vascular flow assessed by 3D power Doppler and adverse pregnancy outcomes

OBJECTIVE To estimate the utility of first-trimester 3D-placental volume and vascular flow indices in the prediction of adverse pregnancy outcomes. METHODS A prospective cohort study including women with singleton pregnancies seen between 11 and 14 weeks as part of a screening program for aneuploidy. Placental volume and vascularization indices were obtained using 3D power Doppler imaging and the VOCAL technique. Placental volume (PV), Vascularization Index (VI), Flow Index (FI) and Vascularization Flow Index (VFI) were calculated. The adverse pregnancy outcomes investigated include preeclampsia (PE), gestational hypertension (GH) and small for gestational age (SGA). The predictive ability of each variable was evaluated using receiver-operating characteristic (ROC) curves. RESULTS Of 388 women included, PE was seen in 30 (7.7%), GH in 37 (9.0%) and SGA in 31 (8.0%). Placental volume was not significantly different between the pregnancies with adverse outcomes and those without. The mean values of the VI and VFI were significantly lower in the pregnancies that developed PE but not in GH or SGA. The area under the ROC curve for the prediction of PE was 0.71, 0.69 and 0.70 for VI, FI and VFI, respectively. CONCLUSION The study confirms lower 3D power Doppler vascular flow indices in pregnancies that develop PE. The discriminatory ability of using these indices alone for predicting PE appears modest.

The effects of obesity on the first stage of labor.

OBJECTIVE: To estimate the effects of obesity on the duration and progression of the first stage of labor in a predominantly obese population and estimate the dose–effect with increasing classes of obesity. METHODS: We performed a retrospective cohort study of labor progression among 5,204 consecutive parturients with singleton term pregnancies (37 weeks of gestation or more) and vertex presentation who completed the first stage of labor. Two comparison groups were defined by body mass index (BMI) less than 30 (n=2,413) or 30 or more (n=2,791). Repeated-measures analysis with polynomial modeling was used to construct labor curves. The duration and progression among women with BMIs less than 30 and BMIs of 30 or more were compared in a multivariable interval-censored regression model adjusting for parity, type of labor onset, race, and birth weight more than 4,000 g. RESULTS: The labor curves indicate longer duration and slower progression of the first stage of labor among women with BMIs of 30 or more for both nulliparous and multiparous women. Multivariable interval-censored regression analysis confirmed significantly longer duration (4–10 cm: 4.7 compared with 4.1 hours, P<.01) and slower progression of cervical dilation from 4 to 6 cm (2.2 compared with 1.9 hours, P<.01 with a range of 0.5–10.0 hours) among women with BMIs of 30 or more after adjusting for confounders. CONCLUSION: The overall duration is longer and progression of the early part of the first stage of labor is slower in obese women. This suggests that obesity should be considered in defining norms for management of labor, particularly in the early part of the first stage. LEVEL OF EVIDENCE: II

IVF outcomes in obese donor oocyte recipients: a systematic review and meta-analysis

STUDY QUESTION Does obesity influence the chance of pregnancy after IVF in donor oocyte recipients? SUMMARY ANSWER The chance of pregnancy after IVF is no different in obese donor oocyte recipients versus those in the normal BMI range. WHAT IS KNOWN ALREADY Obesity is associated with decreased chances of pregnancy in women undergoing IVF with autologous oocytes. Prior studies have investigated the impact of obesity on IVF outcomes in donor oocyte recipients, with disparate results. This is the first systematic review and meta-analysis to address this topic. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis of published literature identified in Medline, EMBASE and Scopus through December of 2011 were performed to address the association between BMI and outcomes for donor oocyte recipients. The primary outcome of this study was implantation. PARTICIPANTS/MATERIALS, SETTING, METHODS Two authors conducted the searches independently, selected the studies and abstracted the data. Studies in English of first donor oocyte cycles with reported recipient BMI were included. Primary data collected from the IVF program at Washington University were also included as one study (n = 123 donor oocyte recipients). Studies limited to frozen embryo transfer were excluded. Data were synthesized using DerSimonian-Laird random effects models for implantation, clinical pregnancy, miscarriage and live birth. MAIN RESULTS AND THE ROLE OF CHANCE Of 475 screened articles, 7 were reviewed and 5 were included together with primary data from Washington University, giving a total of 4758 women who were included for the assessment of the primary outcome. No associations between obesity (BMI ≥ 30 kg/m(2)) and chance of pregnancy after IVF were noted in women using donor oocytes [risk ratio (RR): 0.98, 95% confidence intervals (CI): 0.83-1.15, I(2): 61.6%]. Additional analyses assessing associations between recipient obesity and embryo implantation (RR: 0.93, 95% CI: 0.80-1.07, I(2): 0%), miscarriage (RR: 1.12, 95% CI: 0.83-1.50, I(2): 0%) and live birth (RR: 0.91, 95% CI: 0.65-1.27, I(2) 47.9%) also failed to show a negative effect. LIMITATIONS, REASONS FOR CAUTION Included studies were small and they were performed in a variety of locations and practice settings where stimulation and laboratory protocols may differ, and extremes of BMI may also differ. Furthermore, included studies had different inclusion and exclusion criteria. These factors could not be controlled for in this meta-analysis and statistical heterogeneity was noted for some outcomes. WIDER IMPLICATIONS OF THE FINDINGS These data suggest obesity does not affect IVF outcomes in women using donor oocytes. Oocyte quality rather than endometrial receptivity may be the overriding factor influencing IVF outcomes in obese women using autologous oocytes. STUDY FUNDING/COMPETING INTEREST(S) E.S.J. and M.G.T receive support from the Womens Reproductive Health Research Program sponsored by the National Institutes of Health (K12 HD063086). The authors do not have any competing interests. TRIAL REGISTRATION NUMBER N/A.

Pomegranate juice and punicalagin attenuate oxidative stress and apoptosis in human placenta and in human placental trophoblasts

The human placenta is key to pregnancy outcome, and the elevated oxidative stress present in many complicated pregnancies contributes to placental dysfunction and suboptimal pregnancy outcomes. We tested the hypothesis that pomegranate juice, which is rich in polyphenolic antioxidants, limits placental trophoblast injury in vivo and in vitro. Pregnant women with singleton pregnancies were randomized at 35∼38 wk gestation to 8 oz/day of pomegranate juice or apple juice (placebo) until the time of delivery. Placental tissues from 12 patients (4 in the pomegranate group and 8 in the control group) were collected for analysis of oxidative stress. The preliminary in vivo results were extended to oxidative stress and cell death assays in vitro. Placental explants and cultured primary human trophoblasts were exposed to pomegranate juice or glucose (control) under defined oxygen tensions and chemical stimuli. We found decreased oxidative stress in term human placentas from women who labored after prenatal ingestion of pomegranate juice compared with apple juice as control. Moreover, pomegranate juice reduced in vitro oxidative stress, apoptosis, and global cell death in term villous explants and primary trophoblast cultures exposed to hypoxia, the hypoxia mimetic cobalt chloride, and the kinase inhibitor staurosporine. Punicalagin, but not ellagic acid, both prominent polyphenols in pomegranate juice, reduced oxidative stress and stimulus-induced apoptosis in cultured syncytiotrophoblasts. We conclude that pomegranate juice reduces placental oxidative stress in vivo and in vitro while limiting stimulus-induced death of human trophoblasts in culture. The polyphenol punicalagin mimics this protective effect. We speculate that antenatal intake of pomegranate may limit placental injury and thereby may confer protection to the exposed fetus.

Loop Electrosurgical Excision Procedure and Risk of Preterm Birth: A Systematic Review and Meta-analysis

OBJECTIVE: To assess whether loop electrosurgical excision procedure (LEEP) increases the risk for preterm birth before 37 weeks of gestation and clarify whether the increased risk for preterm birth is attributable to the procedure itself or to risk factors associated with cervical dysplasia. DATA SOURCES: Two authors performed a search of the relevant data through February 2013 using PubMed, Embase, Scopus, CENTRAL, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We included observational studies that compared rates of preterm birth in women with prior LEEP with women with no history of cervical excision. Nineteen of 559 identified studies met selection criteria. TABULATION, INTEGRATION, AND RESULTS: We compared women with a history of LEEP with two unexposed groups without a history of cervical excision: 1) women with an unknown or no history of cervical dysplasia; and 2) women with a history of cervical dysplasia but no cervical excision. The primary outcome was preterm birth before 37 weeks of gestation. Secondary outcomes were preterm birth before 34 weeks of gestation, spontaneous preterm birth, preterm premature rupture of membranes, and perinatal mortality. DerSimonian-Laird random effects models were used. We assessed heterogeneity between studies using the Q and I2 tests. Stratified analyses and metaregression were performed to assess confounding. Nineteen studies were included with a total of 6,589 patients with a history of LEEP and 1,415,015 without. Overall, LEEP was associated with an increased risk of preterm birth before 37 weeks of gestation (pooled relative risk 1.61, 95% confidence interval [CI] 1.35–1.92). However, no increased risk was found when women with a history of LEEP were compared with women with a history cervical dysplasia but no cervical excision (pooled relative risk 1.08, 95% CI 0.88–1.33). CONCLUSION: Women with a history of LEEP have similar risk of preterm birth when compared with women with prior dysplasia but no cervical excision. Common risk factors for both preterm birth and dysplasia likely explain findings of association between LEEP and preterm birth, but LEEP itself may not be an independent risk factor for preterm birth.

Maternal Obesity and Risk of Postcesarean Wound Complications

OBJECTIVE To estimate the effect of increasing severity of obesity on postcesarean wound complications and surgical characteristics. STUDY DESIGN We performed a retrospective cohort study of consecutive cesarean deliveries at a tertiary care facility from 2004 to 2008. Four comparison groups were defined by body mass index (BMI; kg/cm2): < 30 (n = 728), 30 to 39.9 (n = 1,087), 40 to 49.9 (n = 428), or ≥ 50 (n = 201). The primary outcome was wound complication, defined as wound disruption or infection within 6 weeks postoperatively. Surgical characteristics were compared between groups including administration of preoperative antibiotics, type of skin incision, estimated blood loss (EBL), operative time, and type of skin closure. RESULTS Of the 2,444 women with complete follow-up data, 266 (10.9%) developed a wound complication. Compared with nonobese women (6.6%), increasing BMI was associated with an increased risk of wound complications: BMI 30.0 to 39.9, 9.2%, adjusted odds ratio (aOR) 1.4 (95% confidence interval [CI] 0.99 to 2.0); BMI 40.0 to 49.9, 16.8%, aOR 2.6 (95% CI 1.7 to 3.8); BMI ≥ 50, 22.9%, aOR 3.0 (95% CI 1.9 to 4.9). Increasing BMI was also associated with increased rates of midline vertical incision, longer operative time, higher EBL, and lower rates of subcuticular skin closure. CONCLUSION A dose-response relationship exists between increasing BMI and risk of postcesarean wound complications. Increasing obesity also significantly influences operative outcomes.

Immediate compared with delayed pushing in the second stage of labor: a systematic review and meta-analysis.

OBJECTIVE: To estimate whether immediate or delayed pushing in the second stage of labor optimizes spontaneous vaginal delivery and other perinatal outcomes. DATA SOURCES: We searched electronic databases MEDLINE and CINHAL through August 2011 without restrictions. The search terms used were MeSH headings, text words, and word variations of the words or phrases labor, laboring down, passive descent, passive second stage, physiologic second stage, spontaneous pushing, pushing, or bearing down. METHODS OF STUDY SELECTION: We searched for randomized controlled trials comparing immediate with delayed pushing in the second stage of labor. The primary outcome was spontaneous vaginal delivery. Secondary outcomes were instrumental delivery, cesarean delivery, duration of the second stage, duration of active pushing, and other maternal and neonatal outcomes. Heterogeneity was assessed using the Q test and I2. Pooled relative risks (RRs) and weighted mean differences were calculated using random-effects models. TABULATION, INTEGRATION, AND RESULTS: Twelve randomized controlled trials (1,584 immediate and 1,531 delayed pushing) met inclusion criteria. Overall, delayed pushing was associated with an increased rate of spontaneous vaginal delivery compared with immediate pushing (61.5% compared with 56.9%, pooled RR 1.09, 95% confidence interval [CI] 1.03–1.15). This increase was smaller and not statistically significant among high-quality studies (59.0% compared with 54.9%, pooled RR 1.07, 95% CI 0.98–1.26) but larger and statistically significant in lower-quality studies (81.0% compared with 71.0%%, pooled RR 1.13, 95% CI 1.02–1.24). Operative vaginal delivery rates were high in most studies and not significantly different between the two groups (33.7% compared with 37.4%, pooled RR 0.89, 95% CI 0.76–1.06). Delayed pushing was associated with prolongation of the second stage (weighted mean difference 56.92 minutes, 95% CI 42.19–71.64) and shortened duration of active pushing (weighted mean difference −21.98 minutes, 95% CI −31.29 to −12.68). CONCLUSION: Studies to date suggest there are few clinical differences in outcomes with immediate compared with delayed pushing in the second stage of labor, especially when high-quality studies are pooled. Effects on maternal and neonatal outcomes remain uncertain.

Risk of stillbirth after 37 weeks in pregnancies complicated by small-for-gestational-age fetuses

OBJECTIVE The evidence for delivering small-for-gestational-age (SGA) fetuses at 37 weeks remains conflicting. We examined the risk of stillbirth per week of gestation beyond 37 weeks for pregnancies complicated by SGA. STUDY DESIGN Singleton pregnancies undergoing routine second trimester ultrasound from 1990-2009 were examined retrospectively. The risk of stillbirth per 10,000 ongoing SGA pregnancies with 95% confidence intervals (CIs) was calculated for each week of gestation ≥37 weeks. Using a life-table analysis with correction for censoring, conditional risks of stillbirth, cumulative risks of stillbirth per 10,000 ongoing SGA pregnancies and relative risks (RRs) were calculated with 95% CIs for each week of gestation. RESULTS Among 57,195 pregnancies meeting inclusion criteria the background risk of stillbirth was 56/10,000 (95% CI, 42.3-72.7) with stillbirth risk for SGA pregnancies of 251/10,000 (95% CI, 221.2-284.5). The risk of stillbirth after the 37th week was greater compared with pregnancies delivered in the 37th week (47/10,000, 95% CI, 34.6-62.5 vs 21/10,000, 95% CI, 13.0-32.1; RR, 2.2; 95% CI, 1.3-3.7). The cumulative risk of stillbirth rose from 28/10,000 ongoing SGA pregnancies at 37 weeks to 77/10,000 at 39 weeks (RR, 2.75; 95% CI, 1.79-4.2). Among pregnancies complicated by SGA <5% the cumulative risk of stillbirth at 38 weeks was significantly greater than the risk at 37 weeks (RR, 2.3; 95% CI, 1.4-3.8). CONCLUSION There is a significantly increased risk of stillbirth in pregnancies complicated by SGA delivered after the 37th week. Given these findings, we advocate a policy of delivery of SGA pregnancies 37-38 weeks.