Alka Shaunik

Risk factors for spontaneous abortion in early symptomatic first-trimester pregnancies

OBJECTIVE: To evaluate the association of an ultimate diagnosis of miscarriage with various clinical symptoms and historical factors in a cohort of women presenting with pain, bleeding, or both in the first trimester of pregnancy. METHODS: This was a case–control study from a population of women presenting for care with pelvic pain or vaginal bleeding in the first trimester of pregnancy whose diagnoses were not definite upon initial evaluation. Analyses were performed in 2 ways. In one instance cases were defined as women ultimately definitively diagnosed with a miscarriage and controls were defined as women with a pregnancy that did not result in miscarriage (ectopic pregnancy or ongoing intrauterine pregnancy). The second analysis compared women with a miscarriage only to women who had an ongoing intrauterine pregnancy. RESULTS: A total of 2,026 women were evaluated, with 1,192 ultimately diagnosed with a spontaneous abortion, 367 with ectopic pregnancy, and 467 with a viable intrauterine pregnancy. Although many risk factors were individually associated with miscarriage in preliminary analysis, in the final analysis only extremes in age (< 25 and > 35) and the complaint of bleeding (odds ratio [OR] 7.35, 95% confidence interval[CI] 5.74–9.41) were associated with miscarriage. The complaint of pain (OR 0.72, 95% CI 0.57–0.92), human chorionic gonadotropin (hCG) value greater than 500 (hCG ≤ 500 IU/mL compared with hCG 501–2000: OR 0.52, 95% CI 0.39–0.69) and concurrent cervical infection (OR 0.69, 95% CI 0.55–0.88) were negatively associated with miscarriage. CONCLUSION: Few factors predict miscarriage in women who present with a symptomatic first trimester pregnancy of unknown location. Heavy bleeding was most strongly associated with miscarriage. Concurrent cervical infections should not be overlooked as a cause of bleeding in early pregnancy and were not associated with miscarriage. LEVEL OF EVIDENCE: II-2

Proteomic analysis of serum yields six candidate proteins that are differentially regulated in a subset of women with endometriosis.

OBJECTIVE To identify potential novel biomarkers that differ between subjects with and without endometriosis and that might aid in developing a noninvasive, serum-based diagnostic test. DESIGN Case-control evaluation of a diagnostic test. SETTING University medical center. PATIENT(S) Consenting women of reproductive age undergoing laparoscopy for indications of pain, infertility, elective tubal ligation, tubal reanastomosis, or other benign indication. INTERVENTION(S) Diagnostic laparoscopy and peripheral venipuncture. MAIN OUTCOME MEASURE(S) Concentrations of low-molecular-weight proteins in serum; surgical staging of endometriosis. RESULT(S) Six proteins were found that were differentially expressed between those with and without disease and that had good diagnostic properties. Taken together in a two-step diagnostic algorithm, we were able to diagnose 55% of subjects, with 99% accuracy as to the status of disease. Further combining this algorithm with that derived by our previous study of serum putative markers (monocyte chemoattractant protein-1, migration inhibitory factor, leptin, and CA-125) improved our diagnostic capability to 73% of subjects, with 94% overall accuracy. CONCLUSION(S) This study is the critical first step in the identification of potential novel biomarkers of endometriosis. Future identification of the proteins and further validation in a second population is needed before applying these findings in clinical practice.

Correlation of Telomere Length and Telomerase Activity with Occult Ovarian Insufficiency.

BACKGROUND Occult ovarian insufficiency is associated with infertility, impaired response to ovarian stimulation, and reduced live birth rates in women treated with assisted reproductive technologies. Although a decline in ovarian follicle number is expected with age, the proximate causes of occult ovarian insufficiency in young women remain poorly understood. Abnormalities in telomere length and telomerase activity in human granulosa cells may serve as molecular markers for this condition. METHODS A cross-sectional study was performed. Subjects (37 yr old or less) undergoing in vitro fertilization were classified as cases of occult ovarian insufficiency or controls with mechanical infertility (male or tubal factor). Granulosa cells were acquired at the time of oocyte retrieval to quantify telomere length and telomerase activity. RESULTS Fifty-four women were enrolled. Human granulosa cell telomerase activity was demonstrated, and lack of granulosa cell telomerase activity was associated with occult ovarian insufficiency (odds ratio, 11.0; 95% confidence interval, 1.3-495.6; P = 0.02). Telomeres were shorter in women with occult ovarian insufficiency than in controls (relative telomere/single copy gene ratio, 1.88 vs. 3.15; P = 0.039). CONCLUSIONS Aberrant telomere homeostasis is associated with occult ovarian insufficiency in young women. This finding is consistent with the presence of telomeric attenuation that has been shown in multiple age-related conditions.

Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules

OBJECTIVE To investigate the accuracy of serial hCG to predict outcome of a pregnancy of unknown location in an ethnically and geographically diverse setting. DESIGN Multisite cohort study. SETTING University hospital. PATIENT(S) Women with a pregnancy of unknown location. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Patients were followed until diagnosed with ectopic pregnancy (EP), intrauterine pregnancy (IUP), or miscarriage. To predict outcome, observed hCG level was compared with recommended thresholds to assess deviation from defined normal curves. Predicted outcome was compared with standard of care. Sensitivity, specificity, predictive value, and accuracy were calculated, stratified by diagnosis. RESULT(S) The final diagnosis of 1,005 patients included 179 EPs, 259 IUPs, and 567 miscarriages. The optimal balance in sensitivity and specificity used the minimal expected 2-day increase in hCG level of 35%, and the minimal 2-day decrease in hCG level of 36%-47% (depending on the level) achieving 83.2% sensitivity, 70.8% specificity to predict EP. However, 16.8% of EPs and 7.7% of IUPs would be misclassified solely using serial hCG levels. Consideration of a third hCG and early ultrasound decreased IUP misclassification to 2.7%. CONCLUSION(S) Solely using serial hCG values can result in misclassification. Clinical judgment should trump prediction rules and continued surveillance with a third hCG may be prudent, especially when initial values are low or when values are near suggested thresholds.

Development of a Multiple Marker Test for Ectopic Pregnancy

OBJECTIVE: Many serum markers have been proposed to aid in the identification of an ectopic pregnancy, but few have been validated. Most studies have been limited by sample size and design. The goal of this study was to assess putative markers to identify which can be optimally combined. METHODS: We conducted a case–control study using sera from 100 patients with ectopic pregnancy and 100 patients with intrauterine pregnancy who presented to three urban academic centers between September 2000 and April 2009 with first-trimester pain or bleeding. Samples were analyzed for 12 promising biomarkers. Classification tree analysis was used to examine markers simultaneously with the goal of optimizing the accuracy of ectopic pregnancy diagnosis, and validation was performed using bootstrapping. RESULTS: Six of the 12 markers were differentially expressed between those with ectopic pregnancy and intrauterine pregnancy (P<.001) with fair diagnostic properties (area under the curve greater than 0.6) when examined individually (inhibin A, progesterone, activin A, vascular endothelial growth factor [VEGF], pregnancy-specific &bgr;-1-glycoprotein, and pregnancy-associated plasma protein-A). Six additional markers were found to have limited value. Using a two-step diagnostic algorithm with four markers (progesterone, VEGF, inhibin A, activin A), we diagnosed 42% of the sample with perfect specificity and 98% (93–100%) sensitivity. Overall, a single ectopic pregnancy was misclassified, achieving 99% (96–100%) accuracy. CONCLUSION: Evaluating a large number of biomarkers simultaneously demonstrates that most of the putative markers of ectopic pregnancy are not useful. However, a select few can distinguish ectopic pregnancy from intrauterine pregnancy with superior accuracy as part of a multiple marker test. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00194168. LEVEL OF EVIDENCE: II

Utility of dilation and curettage in the diagnosis of pregnancy of unknown location

OBJECTIVE We sought to determine utility of uterine evacuation for diagnosis of nonviable pregnancy of unknown location (PUL). STUDY DESIGN We conducted a cohort study to assess the prevalence of ectopic pregnancy (EP), overall, and stratified by presenting signs and symptoms in women with a nonviable PUL. RESULTS Of the 173 women, 66 (38%) had miscarriage (spontaneous abortion [SAB]) and 107 (62%) had EP. When initial human chorionic gonadotropin (hCG) was <2000 mIU/mL, the odds of an EP were greater (odds ratio, 4.32; 95% confidence interval, 2.04-9.12). Demographic factors, obstetric history, and clinical presentation were not useful in distinguishing between EP and SAB. Pre-evacuation hCG increase had strong trend association with EP (odds ratio, 2.14; 95% confidence interval, 0.98-4.68). A >30% fall in postcurettage hCG was suggestive, but was not a diagnostic indicator of SAB. CONCLUSION Uterine evacuation is a useful diagnostic aid for women with nonviable PUL. Nondiagnostic ultrasound findings and absolute and serial hCG values are associated with, but do not accurately predict final diagnosis.

A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy

OBJECTIVE To evaluate the performance of a novel biomarker, a disintegrin and metalloprotease-12 (ADAM-12), to differentiate an ectopic pregnancy (EP) from normal intrauterine pregnancies (IUPs). DESIGN Case-control study. SETTING Three urban academic centers. PATIENT(S) Women who were seen in the emergency department with pain or bleeding in the first trimester of pregnancy. INTERVENTION(S) Sera from women with diagnosed EP or IUP were evaluated via proteomics and an ADAM-12 dissociation-enhanced lanthanide fluoroimmunoassay. MAIN OUTCOME MEASURE(S) Differences between groups, area under the receiver operating curve, sensitivity, and specificity. RESULT(S) Via a proteomics evaluation, we found a statistically significant decrease in ADAM-12 in the sera of patients with EP, which we confirmed in a larger group of 199 patients (median IUP 18.6 ng/mL versus median EP 2.5 ng/mL with good discrimination between the groups as assessed by receiver operating characteristics [area under the curve = 0.82]). At a low cut-point, the sensitivity was 70% and specificity 84%, but, at a higher cut-point optimizing sensitivity, the ADAM-12 test demonstrated a sensitivity of 97%. CONCLUSION(S) ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings. Further studies in additional patient populations and in combination with other biomarkers are needed.

Clinical Factors Affecting the Accuracy of Ultrasonography in Symptomatic First-Trimester Pregnancy

OBJECTIVE: To evaluate factors associated with accuracy of initial ultrasonography in patients with symptomatic first-trimester pregnancy. METHODS: Ultrasound diagnosis in the emergency department was compared with an ultimate clinical diagnosis in women in need of a gynecologic consult. The sensitivity, specificity, positive predictive values, and accuracy of the initial ultrasound impression were calculated and stratified by criteria of diagnosis, serum human chorionic gonadotropin (hCG) levels, pain, and bleeding. RESULTS: Eighteen hundred eighty women were evaluated. Overall accuracy of initial ultrasound diagnosis was 78%. A probable ultrasound diagnosis of ectopic pregnancy (adnexal mass without the presence of a yolk sac or embryo) resulted in a higher sensitivity (42.1% compared with 13.2%: P<.001) but a lower positive predictive value (82.7% compared with 98%: P<.01) compared with a definite diagnosis. A probable ultrasound diagnosis of intrauterine pregnancy (double decidual sign without yolk sac or embryo) resulted in a higher sensitivity (36.0% compared with 4.0%; P<.001) and lower positive predictive value (58.8% compared with 87.0%; P>.001) compared with a definite diagnosis. The sensitivity (34.3% compared with 75.9%; P<.01) and positive predictive value (80.4% compared with 91.5%; P=.02) were lower for diagnosis of ectopic pregnancy when serum hCG level was less than 2,000 milli-international units/mL. Ultrasonography was less accurate when bleeding was the chief complaint (72.7% compared with 84.8% P<.006) but not substantially altered by pain as a chief complaint (78.0 compared with 77.8% P>.99). CONCLUSION: A substantial number of misdiagnoses can occur when initial ultrasound diagnosis of intrauterine pregnancy or ectopic pregnancy is made without evidence of a yolk sac or embryo, when hCG values are low, or when a patient has significant bleeding. LEVEL OF EVIDENCE: II

Is factor V Leiden mutation a cause of in vitro fertilization failure

This prospective cohort study tested whether the most common hereditary thrombophilia, factor V Leiden (FVL) mutation, is associated with nonpregnancy after IVF. Factor V Leiden mutation prevalence was very low (1.6%) and had a preliminarily positive association with pregnancy, suggesting that routine testing in a general IVF population for FVL mutation as a cause of IVF failure and infertility is not indicated.

Conservative management of vesicouterine fistula after uterine rupture

We report the closure of a vesicouterine fistula with conservative management utilizing an indwelling transurethral Foley catheter. Uterine rupture occurred during a trial of vaginal birth after cesarean section, necessitating an emergency cesarean section. Upon entry into the abdomen, the base of the bladder was noted to be involved in the uterine rupture. The bladder trigone and ureteral orifices appeared normal. A primary, two-layer bladder repair was performed. A cystogram on postoperative day 14 demonstrated a vesicouterine fistula. Conservative management involving bladder drainage for 21 days with a transurethral Foley catheter was successful in closure of the fistula.Vesicouterine fistula, a documented complication of uterine rupture due to attempted vaginal birth after previous cesarean section, can spontaneously resolve with conservative management alone.