Chapter 6: assessing applicability of medical test studies in systematic reviews.

Use of medical tests should be guided by research evidence about the accuracy and utility of those tests in clinical care settings. Systematic reviews of the literature about medical tests must address applicability to real-world decision-making. Challenges for reviews include: (1) lack of clarity in key questions about the intended applicability of the review, (2) numerous studies in many populations and settings, (3) publications that provide too little information to assess applicability, (4) secular trends in prevalence and the spectrum of the condition for which the test is done, and (5) changes in the technology of the test itself. We describe principles for crafting reviews that meet these challenges and capture the key elements from the literature necessary to understand applicability.

First-trimester bleeding characteristics associate with increased risk of preterm birth: data from a prospective pregnancy cohort.

BACKGROUND: Prior evidence linking first-trimester bleeding with preterm birth (PTB, <37 weeks gestation) risk has been inconsistent and may be biased by subject selection and/or incomplete documentation of bleeding episodes for all participants. Prior studies have not carefully examined the role of bleeding characteristics in PTB risk. In the present study, we estimate the association between first-trimester bleeding and PTB in a non-clinical prospective cohort and test whether bleeding characteristics better predict risk. METHODS: Women were enrolled in Right from the Start (2000-2009), a prospective pregnancy cohort. Data about bleeding and bleeding characteristics were examined with logistic regression to assess association with PTB. RESULTS: Among 3978 pregnancies 344 were PTB and 3634 term. Bleeding was reported by 986 (26%) participants. After screening candidate confounders, only multiple gestations remained in the model. Bleeding associated with PTB [odds ratio (OR)(adjusted) = 1.40, 95% confidence interval (CI) 1.09-1.80]. Risk did not vary by race/ethnicity. Compared with non-bleeders, PTB risk was higher for bleeding with red color (OR(adjusted) = 1.92, 95% CI, 1.32-2.82), for heavy episodes (OR(adjusted) = 2.40, 95% CI 1.18-4.88) and long duration (OR(adjusted) = 1.67, 95% CI 1.17-2.38). CONCLUSIONS: Bleeding associated with PTB was not confounded by common risk factors for bleeding or PTB. PTB risk was greatest for women with heavy bleeding episodes with long duration and red color and would suggest that combining women with different bleeding characteristics may affect the accuracy of risk assessment. These data suggest a candidate etiologic pathway for PTB and warrant further investigation of the biologic mechanisms.

Ultrasound-derived fetal size nomogram for a sub-Saharan African population: a longitudinal study.

OBJECTIVES: To create a fetal size nomogram for use in sub-Saharan Africa and compare the derived centiles with reference intervals from developed countries. METHODS: Fetal biometric measurements were obtained at entry to antenatal care (11-22 weeks' gestation) and thereafter at 4-week intervals from pregnant women enrolled in a longitudinal ultrasound study in Kinshasa, Democratic Republic of Congo. The study population comprised 144 singleton gestations with ultrasound-derived gestational age within 14 days of the menstrual estimate. A total of 755 monthly ultrasound scans were included with a mean +/- SD of 5 +/- 1 (range, 2-8) scans per woman. Estimated fetal weight (EFW) was calculated at each ultrasound examination using the Hadlock algorithm. A general mixed-effects linear regression model that incorporated random effects for both the intercept and slope was fitted to log-transformed EFW to account for both mean growth and within-fetus variability in growth. Reference centiles (5(th), 10(th), 50(th), 90(th) and 95(th) centiles) were derived from this model. RESULTS: Nomograms derived from developed populations consistently overestimated the 50(th) centile EFW value for Congolese fetuses by roughly 5-12%. Differences observed in the 10(th) and 90(th) centiles were inconsistent between nomograms, but generally followed a pattern of overestimation that decreased with advancing gestational age. CONCLUSIONS: In low-resource settings, endemic malaria and maternal nutritional factors, including low prepregnancy weight and pregnancy weight gain, probably lead to lower fetal weight and utilization of nomograms derived from developed populations is not appropriate. This customized nomogram could provide more applicable reference intervals for diagnosis of intrauterine growth restriction in sub-Saharan African populations.

Impact of maternal malaria and under-nutrition on intrauterine growth restriction: a prospective ultrasound study in Democratic Republic of Congo.

Maternal malaria and under-nutrition are established risk factors for small-for-gestational-age (SGA) births; however, whether malaria is associated with intrauterine growth restriction (IUGR) is unknown. We investigated IUGR risk among 177 HIV-negative pregnant women enrolled in a longitudinal ultrasound study conducted in Democratic Republic of Congo from May 2005 to May 2006. Malaria infection, maternal anthropometrics, and ultrasound estimated fetal weight were measured monthly. All positive malaria cases were treated and intermittent presumptive therapy (IPTp) provided. Log-binomial regression models for IUGR were fitted using generalized estimating equations to account for statistical clustering of repeat IUGR measurements. Twenty-nine percent of fetuses experienced an episode of IUGR with the majority occurring in the third trimester. The risk of IUGR associated with malaria was greatest after three or more cumulative infections (RR 3.3, 95% CI 1.3-8.2) and was two- to eight-fold higher among women with evidence of under-nutrition. Receiving antimalarial treatment in the previous month (for IPTp or treatment) was significantly protective against IUGR (RR 0.5, 95% CI 0.3-0.7). The interaction observed between malaria and under-nutrition suggests that antenatal programmes in malaria endemic areas should incorporate nutritional screening and supplementation in addition to IPTp.

Medicaid reimbursement for prenatal smoking intervention influences quitting and cessation.

BACKGROUND: 40% of births in the USA are covered by Medicaid and smoking is prevalent among recipients. The objective of this study was to evaluate the association between levels of Medicaid coverage for prenatal smoking cessation interventions on quitting during pregnancy and maintaining cessation after delivery. METHODS: Population based survey study of 7513 post-partum women from 15 states who: participated in Pregnancy Risk Assessment Monitoring System (PRAMS) during 1998-2000; smoked at the beginning of their pregnancy; and had Medicaid coverage. Participating states were categorised into three levels of Medicaid coverage for smoking cessation interventions during prenatal care: extensive (pharmacotherapies and counselling); some (pharmacotherapies or counselling); or none. Quit rates among women who smoked before pregnancy and rates of maintaining cessation were examined. RESULTS: Higher levels of coverage during prenatal care for smoking cessation interventions were associated with higher quit rates; 51%, 43%, and 39% of women quit in states with extensive, some, and no coverage, respectively. Compared to women in states with no coverage, women in states with extensive coverage had 1.6 times the odds of quitting smoking (odds ratio (OR) 1.58, 95% confidence interval (CI) 1.00 to 2.49). Maintenance of cessation after delivery was associated with extensive levels of Medicaid coverage; 48% of women maintained cessation in states with extensive coverage compared to 37% of women in states with no coverage. Compared to women in states with no coverage, women with extensive coverage had 1.6 times the odds of maintaining cessation (OR 1.63, 95% CI 1.04 to 2.56). CONCLUSIONS: Prenatal Medicaid coverage for both pharmacotherapies and counselling is associated with higher rates of quitting and continued cessation. This suggests policymakers can promote cessation by broadening smoking cessation services in Medicaid prenatal coverage.

A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH.

In men with a clinical diagnosis of benign prostatic hyperplasia (BPH), polytomous logistic regression analysis was conducted to evaluate associations between two silent polymorphisms in SRD5A1 (codon positions 30 and 116), two polymorphisms in SRD5A2 (Val89Leu substitution and C to T transition in intron 1), a trinucleotide (CAG)n repeat in androgen receptor (AR), and an Arg492Cys substitution in ADRA1A and clinical parameters that characterize severity of BPH. Candidate gene selection was based on two mechanistic pathways targeted by pharmacotherapy for BPH: (1) androgen metabolic loci contributing to prostate growth (static obstruction); and (2) factors affecting smooth muscle tone (dynamic obstruction). Polymorphisms in SRD5A2 were not associated with severity of BPH; however, SRD5A1 polymorphisms were associated with severity of BPH. The process(es) in which these silent single-nucleotide polymorphisms (SNPs) influence BPH phenotypes is unknown and additional studies will be needed to assess whether these SNPs have direct functional consequences. The characterization of additional molecular factors that contribute to static and dynamic obstruction may help predict response to pharmacotherapy and serve to identify novel drug targets for the clinical management of BPH.

Technologic advances for evaluation of cervical cytology: is newer better?

Among those women who have cervical cancer and have been screened, 14% to 33% of the cases represent failure to detect abnormalities that existed at the time of screening. New technologies intended to improve detection of cytologic abnormalities include liquid-based, thin-layer cytology (ThinPrep, AutoCyte), computerized rescreening (PAPNET), and algorithm-based computer rescreening (AutoPap). This report combines evidence reviews conducted for the U.S. Preventive Services Task Force and the Agency for Healthcare Research and Quality, in which we systematically identified articles on cervical neoplasia, cervical dysplasia, and screening published between January 1966 and March 2001. We note the challenges for improving screening methods, providing an overview of methods for collecting and evaluating cytologic samples, and examining the evidence about the diagnostic performance of new technologies for detecting cervical lesions. Using standard criteria for evaluation of the diagnostic tests, we determined that knowledge about the sensitivity, specificity, and predictive values of new technologies is meager. Only one study of liquid-based cytology used a reference standard of colposcopy, with histology as indicated, to assess participants with normal screening results. Lack of an adequate reference standard is the overwhelming reason that test characteristics cannot be properly assessed or compared. Most publications compare results of screening using the new technology with expert panel review of the cytologic specimen. In that case, the tests are not independent measures and do nothing to relate the screening test findings to the true status of the cervix, making determination of false-negatives, and thus sensitivity, specificity, and negative predictive value, impossible. We did not identify any literature about health outcomes or cost effectiveness of using these tools in a system of screening. For the purposes of guiding decision making about choice of screening tools, the current evidence is inadequate to gauge whether new technologies are "better" than conventional cytology..

Disposition of sperm donors with resultant abnormal pregnancies.

We wished to determine how clinicians manage sperm donors whose offspring have chromosomal or structural abnormalities. A directed, multiple-choice survey was given to reproductive endocrinologists and obstetrical geneticists to assess management of sperm donors whose offspring have chromosomal or structural abnormalities. The questionnaire was completed by 66 reproductive endocrinologists and obstetrical geneticists. Abnormalities and the most common inheritance modes included: Trisomy 21 (aneuploidy, maternal origin), Turner syndrome (aneuploidy, paternal origin), cleft lip/palate (multifactorial), VATER sequence (vertebral defects, imperforate anus, tracheo-esophageal fistula, radial and renal dysplasia, sporadic inheritance), and Hurler syndrome (autosomal recessive). Response choices were: (i) remove donor from programme, (ii) inform potential recipients of prior pregnancy outcomes and continue to use donor, or (iii) further study donor to assess karyotype/mutations. Inheritance mode appeared to influence decisions to remove donors from sperm banks; however, no clear consensus was noted. Guidelines exist for screening potential gamete donors, but not for managing donors whose offspring has a chromosomal or structural abnormality. Guidelines must be developed to manage sperm donors with untoward pregnancy outcomes.

Vaginal preparation with povidone iodine and postcesarean infectious morbidity: a randomized controlled trial.

OBJECTIVE: To determine whether vaginal preparation with povidone iodine before cesarean decreased the incidence of postpartum infectious morbidity. METHODS: Participants were randomly assigned to vaginal preparation with povidone iodine (n = 247) or no preparation (n = 251). Postpartum infectious morbidity included fever, defined as temperature of 38C or greater after the day of surgery; endometritis, defined as fever with abdominal or uterine tenderness and initiation of intravenous antibiotics; and wound separation, defined as disruption of the abdominal incision that required wound care. We calculated overall rates of postpartum infectious morbidity, relative risks (RR), and 95% confidence intervals (CI) for the effect of vaginal preparation. As designed and reported, the trial had at least 80% power to detect a 10% or greater absolute difference in rates of overall infectious morbidity, fever, and endometritis (two-tailed, alpha = 0.05). RESULTS: There was no difference between groups in maternal age, parity, race, education, prior cesarean, type of anesthesia, labor before current cesarean, number of vaginal examinations during labor, internal monitoring, prophylactic antibiotic use, gestational age at delivery, or payment status. Excluding 68 women with chorioamnionitis, incidence of postoperative fever was 19.3%, endometritis 7.2%, and wound separation 7.0%. Vaginal preparation with povidone iodine before cesarean had no effect on risk for fever (RR 1.1, 95% CI 0.8, 1.6), endometritis (RR 1.6, 95% CI 0.8, 3.1), or wound separation (RR 0.6, 95% CI 0.3, 1.3). CONCLUSION: Vaginal preparation with povidone iodine before cesarean had no effect on the incidence of fever, endometritis, or wound infection.

Bacterial vaginosis and cervical dilation and effacement at 24-29 weeks' gestation.

The purpose of this study was to investigate the association between bacterial vaginosis (BV) and cervical dilation and effacement, as measures of impending preterm delivery. The Pregnancy, Infection, and Nutrition Study collected genital tract specimens and documented cervical change from 807 eligible women between 24 and 29 weeks' gestation. BV was assessed with Nugent-scored vaginal smears, and analyzed in relation to cervical measurements. At 24-29 weeks' gestation, <7% of women had a dilated cervix, 31% had a cervix < or =2 cm, and 17.3% had BV. Unadjusted analyses found no associations between BV and cervical measurements. Adjusted logistic regression suggested an association between BV and cervical effacement among women with a sexually transmitted disease (STD) earlier in pregnancy (odds ratio = 1.9, 95% CI 0.8-4.3). Stratified analyses for BV/dilation also suggested interaction with STDs. Overall, BV was not association with cervical dilation or effacement at 24-29 weeks' gestation.

Clinical usefulness of white blood cell count after cesarean delivery.

OBJECTIVE: To examine changes in white blood cell (WBC) count after cesarean and estimate risk of postoperative infection. METHODS: We measured complete blood cell counts at admission and on postoperative day 1 for 458 women who had cesareans. Information from charts was abstracted, and definitions of infectious outcomes and fever were applied by three physicians masked to laboratory results. We examined changes in absolute and relative WBC counts by labor status. Likelihood ratios for postoperative infection were calculated for statistically distinct categories of percentage changes. RESULTS: We excluded 60 women with chorioamnionitis. Of the remainder, 34 (8.5%) developed endometritis and three (0.8%) pneumonia. Women who labored before cesarean (n = 198) had higher antepartum (P <.001) and postoperative day 1 (P <.001) WBC counts than those who did not (n = 200). However, change in WBC count after cesarean relative to antepartum was similar for both groups (P =.41), averaging a 22% increase. We grouped percentage changes into the following three levels: up to 24%, 25-99%, and at least 100%. The lowest level (n = 246) corresponded to a category-specific likelihood ratio for diagnosis of serious postpartum infection of 0. 5 (95% confidence interval [CI] 0.3, 0.8), the midlevel (n = 141) to a category-specific likelihood ratio of 1.7 (95% CI 1.2, 2.3), and the highest level (n = 11) to a category-specific likelihood ratio of 5.8 (95% CI 1.8, 18.7). CONCLUSION: Labor influenced postcesarean WBC counts but did not obscure changes associated with infection. Information gained from changes in WBC counts can be used to assess risk of infection.

The use of significant reduction rates to evaluate health education methods for pregnant smokers: a new harm reduction behavioral indicator?

This article evaluates the evidence to support the use of biochemical measurement of significant reduction (SR) rates among pregnant smokers as a new behavioral indicator of "harm reduction" (HR). The results of four studies--three randomized patient education clinical trials of pregnant smokers (Trials I, II, and III) and an epidemiological study (Study IV)--are presented. Among Trial I, II, and III cohorts of pregnant smokers, control group SR rates of 7% (I), 9% (II), and 20% (III) were increased among experimental groups to 17% (I), 18% (II), and 32% (III) by the same patient education methods. Analyses of infant birthweight data in Study IV found that a patient SR rate representing a 50% or more decrease between a baseline and follow-up test was associated with an increase in adjusted birthweight of 92 grams.

A randomized controlled trial of smoking cessation intervention in pregnancy in an academic clinic.

To evaluate the effectiveness of a physician-based intervention to promote smoking cessation during pregnancy, we conducted this randomized controlled trial in the resident-staffed prenatal clinics at the University of North Carolina Women's Hospital . Two hundred fifty prenatal patients who smoked were enrolled at their first visit and randomly assigned to the intervention or the usual-care group. Resident physicians provided self-help materials to intervention subjects and used a script to set goals with them at each prenatal visit. Subjects who set quit dates were contacted by volunteer cessation counselors. To verify smoking status, subjects provided a self-report and breath carbon monoxide (CO) sample at each visit. Controls were similarly assessed at enrollment and at three additional predetermined intervals. Twenty percent of intervention subjects and 10% of controls reported cessation, which was verified by CO level (P = .052). Fifty-one percent of subjects reduced their consumption by half or more, compared with 30% of controls (P = .002). The intervention is effective in promoting smoking cessation and reduction. In addition, this technique is inexpensive, readily accepted by staff, and efficient.