Diurnal differences in milk composition and its influence on in vitro growth of Staphylococcus aureus and Escherichia coli in bovine quarter milk.

In experimental intramammary inoculation studies, it has been observed that mastitis susceptibility is influenced, among others, by cow factors. To identify milk characteristics leading to these differences, quarter milk samples of morning and evening milk were collected and analyzed for their composition (protein, fat, lactose, urea, lactoferrin, lactoperoxidase, and ß-lactoglobulin concentrations), somatic cell count, and antibodies against Staphylococcus aureus. Furthermore, in vitro growth of S. aureus and Escherichia coli in fresh quarter milk samples was determined. All measured parameters differed significantly between quarters and also between morning and evening milk with the exception of lactose levels. In addition, quantitative growth of S. aureus and E. coli was significantly different in morning milk compared with evening milk. Mixed model analysis revealed that replication of S. aureus was negatively associated with the presence of fat, S. aureus-specific IgG1 antibodies, contamination of the milk sample and morning milk. Replication of E. coli was negatively associated with fat concentrations, and positively associated with morning milk. The significant difference between morning and evening milk supports the theory that changes in milk composition influence bacterial growth. Although all determined milk components differed significantly between quarters and in time no significant association with bacterial growth could be identified with the exception of fat for both studied species and IgG1 titers for S. aureus. The negative association of fat with bacterial growth was assumed to occur due to activation of lipolysis by milk handling and can most likely be neglected for in vivo relevance. The fact that S. aureus-specific IgG1 titers were negatively associated with S. aureus growth in vitro encourages the ongoing effort to develop a vaccine against S. aureus-induced mastitis.

Changes in Cesarean section scar dimensions during pregnancy: a prospective longitudinal study.

OBJECTIVES: To describe changes in Cesarean section (CS) scars longitudinally throughout pregnancy, and to relate initial scar measurements, demographic variables and obstetric variables to subsequent changes in scar features and to final pregnancy outcome. METHODS: In this prospective observational study we used transvaginal sonography (TVS) to examine the CS scar of 320 consecutive pregnant women at 11-13, 19-21 and 32-34 weeks' gestation. For scars visible on TVS, the hypoechoic part was measured in three dimensions and the residual myometrial thickness (RMT) was also measured. Analyses were carried out using one-way repeated measures ANOVA and mixed modeling. The incidence of subsequent scar rupture was recorded. RESULTS: The CS scar was visible in 284/320 cases (89%). Concerning length and depth of the hypoechoic part of the scar and RMT, the larger the initial scar measurement, the larger the decrease observed during pregnancy. For the hypoechoic part of the scar, the width increased on average by 1.8 mm per trimester, while the depth and length decreased by 1.8 and 1.9 mm, respectively (false discovery rate P < 0.0001). Mean RMT in the first trimester was 5.2 mm and on average decreased by 1.1 mm per trimester. Two cases (0.62%) of uterine scar rupture were confirmed following a trial of vaginal delivery; these had a mean RMT of 0.5 mm at second scan and an average decrease of 2.6 mm over the course of pregnancy. CONCLUSION: This study establishes reference data and confirms that the dimensions of CS scars change throughout pregnancy. Scar rupture was associated with a smaller RMT and greater decrease in RMT during pregnancy. There is the potential to test absolute values and observed changes in CS scar measurements as predictors of uterine scar rupture and outcome in trials of vaginal birth after Cesarean section.

Visibility and measurement of cesarean section scars in pregnancy: a reproducibility study.

OBJECTIVES: To evaluate the visibility of cesarean section (CS) scars by transvaginal sonography (TVS) in pregnant women, to apply a standardized approach for measuring CS scars and to test its reproducibility throughout the course of pregnancy. METHODS: In this observational cohort study, 320 consecutive pregnant women with a previous cesarean delivery were examined to assess scar visibility by two independent examiners. TVS was carried out at 11-13, 19-21 and 34-36 weeks' gestation. A scar was defined as visible when an area of hypoechogenicity representing myometrial discontinuity at the anterior wall of the lower uterine segment was identified. In a subset of patients (n = 111), visible scars were measured by two independent examiners in three dimensions: scar width, depth and length as well as the residual myometrial thickness (RMT). Descriptive analysis was used to assess scar visibility, and the intraclass correlation coefficient (ICC) was calculated to show the strength of absolute agreement between two examiners for scar measurements. For RMT, a cut-off of 2.4 mm was used and measurement agreement was assessed using Cohen's kappa coefficient. RESULTS: The scar was visible in 284/320 cases (88.8%). Visible scars were significantly associated with anteverted uteri (P < 0.0001). Both examiners had 100% agreement on scar visibility at 12 and 20 weeks' gestation, while agreement was 96% at 34 weeks. The intra- and interobserver agreements for scar measurements were generally good (ICC 0.86 and 0.89, respectively). The kappa coefficient for the RMT was 0.27 in the first trimester, compared with 0.51 and 0.72 in the second and third trimesters, respectively. CONCLUSION: CS scars remain visible in the majority of women throughout pregnancy. They can be reproducibly measured in three dimensions when assessed by TVS in all trimesters of pregnancy. The agreement between two observers for CS scar measurement can be considered good for the first trimester, compared with relatively moderate agreement for the second and third trimesters.

Do pocket-sized ultrasound machines have the potential to be used as a tool to triage patients in obstetrics and gynecology?

OBJECTIVES: To evaluate the performance and potential impact on patient management of a pocket-sized ultrasound machine (PUM) in comparison to high-specification ultrasound machines (HSUM). METHODS: This was an observational cohort study with 204 unselected patients in three categories: 1) women with pain and bleeding in early pregnancy (101 patients); 2) women presenting for routine obstetric ultrasound assessment (53 patients); 3) women with possible gynecological pathology (50 patients). Scans were carried out transabdominally using a PUM. A second operator repeated the examination transvaginally and/or transabdominally, depending on the clinical indication, using an HSUM. The operators were blind to each other's findings. RESULTS: In the early pregnancy group, there was good to very good agreement between the PUM and HSUM for identifying the presence or absence of an embryo, gestational sac, fetal heart motion, pregnancy location and final diagnostic outcome (kappa coefficients, 0.844, 0.843, 0.729, 0.785 and 0.812, respectively; P < 0.0001). In the obstetric ultrasound group there was good to very good agreement for fetal presentation, placental location and placental position (kappa coefficients, 0.924, 0.924 and 0.647, respectively; P < 0.0001). In the gynecological pathology group, there was very good agreement for final diagnosis and type of ovarian mass (low risk or complex) (kappa coefficients, 0.846 and 0.930, respectively; P < 0.0001). For the measured continuous variables, there was close agreement for crown-rump length, mean sac diameter, femur length and mean diameter of an ovarian mass, but not for endometrial thickness. Neither patient demographics (age, body mass index, ethnicity) nor operator experience and familiarity with a PUM had an impact on agreement between the two machines. If a PUM had been the only equipment available for an initial assessment, only two cases would have led to a suboptimal patient management plan. CONCLUSION: The findings and final diagnosis in the three study groups were similar for both a PUM used transabdominally and an HSUM used transvaginally and/or transabdominally.

Impact of ovulation and implantation timing on first-trimester crown-rump length and gestational age.

OBJECTIVE: To determine the impact of ovulation and implantation timing on first-trimester crown-rump length (CRL) and the derived gestational age (GA). METHOD: One hundred and forty-three women who were trying to conceive were recruited prospectively. The timing of ovulation and implantation and the ovulation to implantation (O-I) interval were established in 101 pregnancies using home urinary tests for luteinizing hormone and human chorionic gonadotropin. In 71 ongoing pregnancies, GA determined by measurement of fetal CRL at 10-14 weeks' gestation was compared with GA based on ovulation and implantation day. First-trimester growth was determined by serial ultrasound scans at 6-7, 8-9 and 10-14 weeks. RESULTS: The median ovulation and implantation days were 16 and 27, respectively, with an O-I interval of 11 days. GA estimated from CRL at 10-14 weeks was on average 1.3 days greater than that derived from ovulation timing. CRL Z-score was inversely related to O-I interval (ρ= -0.431, P=0.0009). There was no significant relationship between CRL growth rate and the difference between observed CRL and expected CRL based on GA from last menstrual period (ρ=0.224, P=0.08). CONCLUSIONS: Early implantation leads to a larger CRL and late implantation to a smaller CRL at 10-14 weeks, independent of CRL growth rate. Implantation timing is a major determinant of fetal size at 10-14 weeks and largely explains the variation in estimates of GA in the first trimester derived from embryonic or fetal CRL.

Does the presence of a cesarean section scar influence the site of placental implantation and subsequent migration in future pregnancies: a prospective case-control study.

OBJECTIVES: To describe placental location in the first trimester of pregnancy and subsequent placental migration in women with and without a history of previous cesarean delivery. METHODS: In this prospective case-control study, placental location was defined according to five anatomical sites in relation to the endometrial cavity. Placental localization was carried out by transabdominal ultrasound between 11 and 14 weeks' gestation. We recruited 738 women who had undergone one or more previous cesarean sections (CS) and 1856 patients without previous cesarean delivery. Comparative analysis was performed of placental location between the two groups, and to assess placental migration of those classified as being low lying at 20 and 32 weeks' gestation. RESULTS: There were significant differences in placental location between the two groups. In the CS group there were significantly more posterior and fewer fundal placentae than in the control group (47.2 vs 31.5% and 4.7 vs 15.5%, respectively). The number of previous cesarean deliveries did not have a significant effect on placental location. There was no significant difference in the incidence of anterior low-lying placenta between groups (1.5 vs 0.9%). Placental migration of the low-lying subtypes was similar in both groups (62 vs 64%). CONCLUSION: The presence of CS scars in the uterus are associated with an increase in the number of posterior placentae and a reduced number that implant in the fundus of the cavity. Migration of a low-lying placenta is independent of the presence of a CS scar in the uterus.

HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm.

BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC-AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer.

Prediction of lymph node involvement in breast cancer from primary tumor tissue using gene expression profiling and miRNAs.

The aim of this study was to investigate whether lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tumor. For this purpose, we selected a very homogeneous patient population to minimize heterogeneity in other tumor and patient characteristics. First, we compared gene expression profiles of primary tumor tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix Human U133 Plus 2.0 microarray chip. A model was built by weighted Least-Squares Support Vector Machines and validated on an internal and external dataset. Next, miRNA profiling was performed on a subset of 82 tumors using Human MiRNA-microarray chips (Illumina). Finally, for each miRNA the number of significant inverse correlated targets was determined and compared with 1000 sets of randomly chosen targets. A model based on 241 genes was built (AUC 0.66). The AUC for the internal dataset was 0.646 and 0. 651 for the external datasets. The model includes multiple kinases, apoptosis-related, and zinc ion-binding genes. Integration of the microarray and miRNA data reveals ten miRNAs suppressing lymph node invasion and one miRNA promoting lymph node invasion. Our results provide evidence that measurable differences in gene and miRNA expression exist between node negative and node positive patients and thus that lymph node involvement is not a genetically random process. Moreover, our data suggest a general deregulation of the miRNA machinery that is potentially responsible for lymph node invasion.

Umbilical artery pulsatility index and fetal abdominal circumference in isolated gastroschisis.

OBJECTIVES: To investigate changes in abdominal circumference (AC) and umbilical artery pulsatility index (UA-PI) with gestation in fetuses with isolated gastroschisis, and to determine whether a relationship exists between UA-PI and fetal AC. METHODS: Data from 58 pregnancies with isolated gastroschisis diagnosed at between 24 and 36 weeks' gestation were included in the study. Z-scores were calculated with respect to expected UA-PI values in normal pregnancies after log-transformation. AC-Z-scores were calculated with respect to expected size in normal pregnancies according to a standard chart. Functional linear discriminant analysis (FLDA) was applied to generate 50(th), 5(th) and 95(th) percentile curves for changes in both AC and UA-PI with gestational age in fetuses with gastroschisis. These curves were compared with the standard curves, as were the means. UA-PI was also plotted against AC. For this relationship, a robust Spearman correlation coefficient was obtained with FLDA. RESULTS: In fetuses with gastroschisis, there was a highly significant negative correlation between UA-PI and AC, normalized for gestation using Z-scores (median correlation coefficient, - 0.289; median P = 0.000023). Moreover, compared with standard curves AC was lower and UA-PI higher in the gestational-age range studied. Both the AC and UA-PI curves showed a significantly different rate of change with gestation compared with the normal ranges. The mean values for fetuses with gastroschisis compared with the standard AC and UA-PI range curves were significantly different for AC throughout gestation, and for UA-PI from 32 weeks' gestation. CONCLUSIONS: In fetal gastroschisis, it is well known that AC tends to be smaller, though UA-PI has not been reported to be abnormal in any consistent way. There is a clear relationship between the fetus's AC for gestation and UA-PI, which is not the case for normally grown fetuses. The data suggest that the growth restriction seen in gastroschisis may be explained by hypoxia, and not simply by the classical explanation of extra-abdominal displacement of the abdominal viscera.

Improving the preoperative classification of adnexal masses as benign or malignant by second-stage tests.

OBJECTIVE: The aim of this study was to establish when a second-stage diagnostic test may be of value in cases where a primary diagnostic test has given an uncertain diagnosis of the benign or malignant nature of an adnexal mass. METHODS: The diagnostic performance with regard to discrimination between benign and malignant adnexal masses for mathematical models including ultrasound variables and for subjective evaluation of ultrasound findings by an experienced ultrasound examiner was expressed as area under the receiver-operating characteristics curve (AUC), sensitivity and specificity. These were calculated for the total study population of 1938 patients with an adnexal mass as well as for subpopulations defined by the certainty with which the diagnosis of benignity or malignancy was made. The effect of applying a second-stage test to the tumors where risk estimation was uncertain was determined. RESULTS: The best mathematical model (LR1) had an AUC of 0.95, sensitivity of 92% and specificity of 84% when applied to all tumors. When model LR1 was applied to the 10% of tumors in which the calculated risk fell closest to the risk cut-off of the model, the AUC was 0.59, sensitivity 90% and specificity 21%. A strategy where subjective evaluation was used to classify these 10% of tumors for which LR1 performed poorly and where LR1 was used in the other 90% of tumors resulted in a sensitivity of 91% and specificity of 90%. Applying subjective evaluation to all tumors yielded an AUC of 0.95, sensitivity of 90% and specificity of 93%. Sensitivity was 81% and specificity 47% for those patients where the ultrasound examiner was uncertain about the diagnosis (n = 115; 5.9%). No mathematical model performed better than did subjective evaluation among the 115 tumors where the ultrasound examiner was uncertain. CONCLUSION: When model LR1 is used as a primary test for discriminating between benign and malignant adnexal masses, the use of subjective evaluation of ultrasound findings by an experienced examiner as a second-stage test in the 10% of cases for which the model yields a risk of malignancy closest to its risk cut-off will improve specificity without substantially decreasing sensitivity. However, none of the models tested proved suitable as a second-stage test in tumors where subjective evaluation yielded an uncertain result.

Effect of cancer prevalence on the use of risk-assessment cut-off levels and the performance of mathematical models to distinguish malignant from benign adnexal masses.

OBJECTIVE: Two logistic regression models have been developed for the characterization of adnexal masses. The goal of this prospective analysis was to see whether these models perform differently according to the prevalence of malignancy and whether the cut-off levels of risk assessment for malignancy by the models require modification in different centers. METHODS: Centers were categorized into those with a prevalence of malignancy below 15%, between 15 and 30% and above 30%. The areas under the receiver-operating characteristics curves (AUC) were compared using bootstrapping. The optimal cut-off level of risk assessment for malignancy was chosen per center, corresponding to the highest sensitivity level possible while still keeping a good specificity. RESULTS: Both models performed better in centers with a lower prevalence of malignant cases. The AUCs of the two models for centers with fewer than 15% malignant cases were 0.97 and 0.95, those of centers with 15-30% malignancy were 0.95 and 0.93 and those of centers with more than 30% malignant cases were 0.94 and 0.92. This decrease in performance was due mainly to the decrease in specificity from over 90 to around 76%. In the centers with a higher percentage of malignant cases, a sensitivity of at least 90% with a good specificity could not be obtained by choosing a different cut-off level. CONCLUSIONS: Overall the models performed well in all centers. The performance of the logistic regression models worsened with increasing prevalence of malignancy, due to a case mix with more borderline and complex benign masses seen in those centers. Because the cut-off of 0.10 is optimal for all three types of center, it seems reasonable to use this cut-off for both models in all centers.

Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicenter observational study.

OBJECTIVES: We studied changes in mean gestational sac diameter (MSD) and embryonic crown-rump length (CRL) in intrauterine pregnancies of uncertain viability (IPUVs). We aimed to establish cut-off values for MSD and CRL growth that could be definitively associated with either viability or miscarriage, and to establish the relationship between growth in MSD and appearance of embryonic structures in the gestational sac. METHODS: One thousand and sixty consecutive IPUVs were recruited prospectively from four London University hospitals: 462 with no yolk sac or embryo, 419 with a yolk sac but no embryo, and 179 with an embryo but no heartbeat visible. IPUV was defined as an empty gestational sac with or without a yolk sac but no embryo seen with MSD < 20 or < 30 mm (depending on center) or an embryo with no heartbeat and CRL < 6 mm or < 8 mm (depending on center). Scans were repeated 7-14 days later. The endpoint was viability at first-trimester screening ultrasonography between 11 and 14 weeks. Change in MSD and CRL between the first and second scans of each pregnancy was compared with respect to viability and appearance of embryonic structures using the two-sample t-test. RESULTS: The study included 359 pregnancies in which a gestational sac with or without embryo was identified at the follow-up scan 7-14 days later. Of these, 192 were viable and 167 non-viable at the 11-14-week scan. MSD growth was significantly higher in viable than non-viable pregnancies (mean 1.003 vs. 0.503 mm/day; P < 0.001, 95% CI of difference 0.403-0.596). A difference in CRL growth was found between the two groups (mean 0.673 vs. 0.148 mm/day; P < 0.001, 95% CI of difference 0.345-0.703). MSD growth of 0.6 mm/day was associated with a specificity for diagnosing miscarriage of 90.1%, a sensitivity of 61.7% and 19 false-positive test results. A cut-off of CRL growth rate of 0.2 mm/day gave a sensitivity of 76.3% and there were no false-positive test results for miscarriage. On repeat scan the failure of either a yolk sac or embryo to be visualized was always associated with miscarriage. CONCLUSION: There is an overlap in MSD growth rates between viable and non-viable IPUV. No cut-off exists for MSD growth below which a viable pregnancy could be safely excluded. A cut-off value for CRL growth of 0.2 mm/day was always associated with miscarriage. These data suggest that criteria to diagnose miscarriage based on growth in MSD and CRL are potentially unsafe. However, finding an empty gestational sac on two scans more than 7 days apart is highly likely to indicate miscarriage, irrespective of growth.

Limitations of current definitions of miscarriage using mean gestational sac diameter and crown-rump length measurements: a multicenter observational study.

OBJECTIVES: There is significant variation in cut-off values for mean gestational sac diameter (MSD) and embryo crown-rump length (CRL) used to define miscarriage, values suggested in the literature ranging from 13 to 25 mm for MSD and from 3 to 8 mm for CRL. We aimed to define the false-positive rate (FPR) for the diagnosis of miscarriage associated with different CRL and MSD measurements with or without a yolk sac in a large study population of patients attending early pregnancy clinics. We also aimed to define cut-off values for CRL and MSD that, on the basis of a single measurement, can definitively diagnose a miscarriage and so exclude possible inadvertent termination of pregnancy. METHODS: This was an observational cross-sectional study. Data were collected prospectively according to a predefined protocol. Intrauterine pregnancy of uncertain viability (IPUV) was defined as an empty gestational sac or sac with a yolk sac but no embryo seen with MSD < 20 or < 30 mm or an embryo with an absent heartbeat and CRL < 6 mm or < 8 mm. We recruited to the study 1060 consecutive women with IPUV. The endpoint was presence or absence of a viable pregnancy at the time of first-trimester screening ultrasonography between 11 and 14 weeks. The sensitivity, specificity, positive and negative predictive values were calculated for potential cut-off values to define miscarriage from MSD 8 to 30 mm with or without a yolk sac and from CRL 3 to 8 mm. RESULTS: Of the 1060 women with a diagnosis of IPUV, 473 remained viable and 587 were non-viable by the time of the 11-14-week scan. In the absence of both embryo and yolk sac, the FPR for miscarriage was 4.4% when an MSD cut-off of 16 mm was used and 0.5% for a cut-off of 20 mm. There were no false-positive test results for miscarriage when a cut-off of MSD ≥ 21 mm was used. If a yolk sac was present but an embryo was not, the FPR for miscarriage was 2.6% for an MSD cut-off of 16 mm and 0.4% for a cut-off of 20 mm, with no false-positive results when a cut-off of MSD ≥ 21 mm was used. When an embryo was visible with an absent heartbeat, using a CRL cut-off of 4 mm the FPR for miscarriage was 8.3%, and for a CRL cut-off of 5 mm it was also 8.3%. There were no false-positive results using a CRL cut-off of ≥ 5.3 mm. CONCLUSIONS: These data show that some current definitions used to diagnose miscarriage are potentially unsafe. Current national guidelines should be reviewed to avoid inadvertent termination of wanted pregnancies. An MSD cut-off of > 25 mm and a CRL cut-off of > 7 mm could be introduced to minimize the risk of a false-positive diagnosis of miscarriage.

Lidocaine does not reduce pain perception during gel instillation sonography or subsequent office hysteroscopy: results of a randomized trial.

BACKGROUND: To evaluate if the addition of lidocaine to the gel used for gel infusion sonohysterography (GIS) reduces pain experienced during GIS or subsequent hysteroscopy. METHODS: A total of 142 consecutive patients were randomized using computer-generated random integers. In 79 patients, GIS was performed with a gel containing lidocaine (Instillagel®) and in 63 patients the gel did not contain lidocaine (Endosgel®). Immediately after GIS, 132 patients (94%) underwent office hysteroscopy. The women were asked to fill in a questionnaire including a 100-mm visual analogue scale (VAS) score after each examination. RESULTS: The mean age (SD) was 50.8 (12.1) years; 58.5% were premenopausal and 15.6% were nulliparous. The median (interquartile range (IR)) VAS score during GIS for all women was 6 (19.5): 8 (21) for the lidocaine group versus 5 (18.2) for those who received gel without lidocaine. The median (IR) VAS scores during hysteroscopy in the total group, the Instillagel group and the Endosgel group were 15.5 (43.2), 24 (35) and 9 (52), respectively. None of the differences were statistically significant. CONCLUSION: The addition of lidocaine to the gel used either for GIS or prior to office hysteroscopy does not reduce the procedure-related pain.

No influence of body mass index on first trimester fetal growth.

BACKGROUND: Our objective was to determine what effect maternal BMI has on fetal growth rate in the early first trimester. METHODS: This was a prospective observational study of singleton pregnancies with certain dates, initially presenting for a transvaginal scan (TVS) before 12 weeks of gestation. Maternal characteristics (BMI, ethnicity, maternal age, obstetric history, abdominal pain and vaginal bleeding) were recorded. Fetal crown-rump length (CRL) was measured at the initial scan, and at subsequent ultrasound assessments. In order to assess the fetal growth rates, women with at least two CRL measurements were included in the analysis. A mixed-linear effects model analysis was performed to determine whether BMI influences the rate of change in CRL. RESULTS: A total of 264 pregnancies were analysed. The median BMI was 23.55 (range 16-45), median age was 32 (17-44) and the proportion of white, black and Asian women was 61.0, 15.5 and 5.3%, respectively. Mean gestational age (GA) at first TVS was 56 (range 33-84) days. Studying CRL as a function of GA with a mixed-linear effects model showed that this relationship was neither significantly influenced by BMI when modelling BMI as a continuous variable (P = 0.7529), nor when modelling it as a categorical variable using the WHO criteria (P = 0.8904). CONCLUSIONS: Dating by CRL influences subsequent growth assessment and previous studies have suggested that first trimester fetal growth rates may be influenced by ethnicity and age. Our data however suggest that maternal BMI does not significantly influence early fetal growth.

New crown-rump length curve based on over 3500 pregnancies.

OBJECTIVES: The Robinson and Hadlock crown-rump length (CRL) curves are commonly used to estimate gestational age (GA) based on the CRL of an embryo or fetus. However, the Robinson curve was derived from a small population using transabdominal sonography and the Hadlock curve was generated using early transvaginal ultrasound equipment. The aim of this study was to use transvaginal and transabdominal ultrasound to study a large population of early pregnancies to assess embryonic or fetal size, and so create a new normal CRL curve from 5.5 weeks' gestation. We compared this with the Robinson and Hadlock CRL curves. METHODS: A retrospective database study of CRL in first-trimester embryos was conducted in a fetal medicine referral center with a predominantly Caucasian population. Linear mixed-effects analysis was performed to determine the relationship between CRL and GA. After internal validation of this curve, the CRL was compared with the expected CRL at a given GA according to both the Robinson and Hadlock models based on the paired t-test. Bland-Altman plots were constructed to compare the CRL measurements obtained in our study population with those predicted according to GA by both the Robinson and Hadlock curves. RESULTS: In total 3710 normal singleton pregnancies with a known last menstrual period were included in the study, corresponding to 4387 scans. Our data differed significantly from both the Robinson and the Hadlock curves (paired t-test, P < 0.0001). A mixed-effects model for CRL as a function of GA was developed on 70% of the data and internally validated with z-scores on the remaining 30%. The new curve extended from 5.5 to 14 weeks' gestation. Compared to our CRL curve, the Robinson curve gave a 4-day underestimation of GA at 6 weeks with a difference in CRL of 3.7 mm and a 1-day overestimation from 11 to 14 weeks with a difference in CRL of 0.9-1 mm. A comparison between our curve and the Hadlock curve showed a difference in CRL of 2.7 mm at 6 weeks, equivalent to an underestimation of 3 days, and a difference in CRL of 4.8 mm at 14 weeks, equivalent to an overestimation of 2 days. At 9 weeks all three curves were similar. CONCLUSION: The new CRL curve suggests differences in the range of CRL measurements compared with the Robinson and Hadlock curves. These differences are most significant at the beginning and the end of the first trimester, and may lead to more accurate estimations of GA.

The relationship between first trimester fetal growth, pregnancy-associated plasma protein A levels and birthweight.

OBJECTIVE: We sought to define the relationship between first trimester fetal growth, pregnancy-associated plasma protein A (PAPP-A) levels and birthweight. METHODS: Two-hundred and one women with repeat first trimester crown-rump length (CRL) measurements were included. In 194, the first trimester PAPP-A value was known and in 169 there was complete data including birthweight. Fetal growth curves were derived using functional linear discriminant analysis (FLDA) and growth compared between those with < 10th percentile, 10th to 90th and > 90th percentile PAPP-A multiple of median (MoM) levels and birthweight percentiles. RESULTS: Median maternal age was 35 years, gestation at PAPP-A sampling and of first scan was 11 weeks. Median delivery gestation was 40 weeks and birthweight 3425 g. There was no association between first trimester fetal CRL growth and either PAPP-A MoM percentile or birthweight percentile. There was a significant positive correlation between PAPP-A MoM and birthweight percentile (p = 0.0004). CONCLUSIONS: First trimester fetal growth rate is not related to birthweight percentile or first trimester PAPP-A levels. Irrespective of gestation, a low PAPP-A is associated with delivery of a smaller baby, and a high PAPP-A with a larger baby.

Functional linear discriminant analysis: a new longitudinal approach to the assessment of embryonic growth.

BACKGROUND: Functional linear discriminant analysis (FLDA) is a new growth assessment technique using serial measurements to discriminate between normal and abnormal fetal growth. We used FLDA to assess and compare growth in live pregnancies destined to miscarry with those remaining viable. METHODS: This was a prospective cohort study of women with ultrasound scans on at least two separate occasions showing live pregnancies. Serial crown-rump length (CRL), mean gestational sac diameter and mean yolk sac diameter measurements were recorded. The ability of FLDA to predict subsequent miscarriage was compared with that of a single CRL measurement. RESULTS: Of 521 included pregnancies, 493 (94.6%) remained viable at 14 weeks and 28 (5.4%) miscarried. The CRL growth rate was significantly lower in those that miscarried (one-sample t-test, P = 2.638E-22). The sensitivity of FLDA in predicting miscarriage from serial CRL measurements was 60.7% and specificity was 93.1% [positive predictive value (PPV) 33.3%, negative predictive value (NPV) 97.7%]. This was significantly better for predicting miscarriage than a single CRL observation of more than 2SD below that expected (sensitivity 53.6%, specificity 72.2%, PPV 9.9%, NPV 96.5%). CONCLUSIONS: FLDA discriminates between normal and abnormal growth to predict miscarriage with high specificity. FLDA predicts miscarriage better than a single observation of a small CRL.

Gel infusion sonography in the evaluation of the uterine cavity.

OBJECTIVES: To compare gel infusion sonohysterography (GIS) with saline contrast sonohysterography (SCSH) with regard to technical feasibility and procedure-related pain experienced by patients. METHODS: This prospective observational cohort study included 551 consecutive patients with abnormal bleeding: SCSH was attempted in the first 402 women and GIS was attempted in the following 149. All procedures were performed by the same examiner, in the same clinical setting, using a 2-mm diameter catheter. After contrast sonohysterography, most patients underwent office hysteroscopy (n = 502) and endometrial sampling (n = 323). The women were asked to rate the pain experienced during each procedure using a 100-mm visual analog scale (VAS). Patients' characteristics, ultrasound findings, histological diagnosis, technical failures and procedure-related pain were compared between the two procedures. RESULTS: The mean +/- SD VAS score for contrast sonography, subsequent hysteroscopy and endometrial biopsy were 22.9 +/- 21.7, 38.8 +/- 26.6 and 50.0 +/- 26.3, respectively, in the SCSH subgroup vs. 16.5 +/- 21.5, 27.6 +/- 28 and 33.6 +/- 30.3, respectively, in the GIS subgroup (P = 0.0051, P = 0.0005 and P = 0.0003, respectively). The technical failure rate was 5% in the SCSH subgroup vs. 2% in the GIS subgroup (P = 0.1522). CONCLUSIONS: GIS and SCSH showed similar technical feasibility. The procedure-related pain reported by patients during contrast sonohysterography, as well as during subsequent hysteroscopy and endometrial sampling, was less in the GIS group.

Ultrasound methods to distinguish between malignant and benign adnexal masses in the hands of examiners with different levels of experience.

OBJECTIVES: To determine the effect of an ultrasound training course on the performance of pattern recognition when used by less experienced examiners and to compare the performance of pattern recognition, a logistic regression model and a scoring system to estimate the risk of malignancy between examiners with different levels of experience. METHODS: Using ultrasound images of selected adnexal masses, two trainees classified the masses as benign or malignant by using pattern recognition both before and after they had attended a theoretical gynecological ultrasound course. They also classified the masses by using a logistic regression model and a scoring system, but only after they had attended the course. The performance of these three methods when they were used by the trainees was then compared with that when they were used by experts. RESULTS: One hundred and sixty-five adnexal masses were included, of which 42% were malignant (21% invasive tumors and 21% borderline tumors). The area under the receiver-operating characteristics curve of pattern recognition when used by the trainees was similar before and after they had attended the course. Training decreased sensitivity (84% vs. 70% for Trainee 1, P = 0.004; 70% vs. 61% for Trainee 2, P = 0.058) and increased specificity (77% vs. 92% for Trainee 1, P = 0.001; 89% vs. 95% for Trainee 2, P = 0.058). The performance of pattern recognition was poorer in the hands of the trainees than in the hands of the experts. The sensitivities of the logistic regression model were 70% and 54% for the trainees vs. 83% for an expert (P = 0.020 and < 0.001, respectively) and the specificities were 84% and 94% vs. 89% (P = 0.25 and 0.59, respectively). The sensitivities of the scoring system were 59% and 54% for the trainees vs. 75% for the expert (P = 0.002 and < 0.001, respectively), and the specificities were 90% and 93% vs. 85% (P = 0.103 and 0.008, respectively). CONCLUSION: Theoretical ultrasound teaching did not seem to improve the performance of pattern recognition in the hands of trainees. A logistic regression model and a scoring system to classify adnexal masses as benign or malignant perform less well when they were used by inexperienced examiners than when used by an expert. Before using a model or a scoring system, experience and/or proper training are likely to be of paramount importance if diagnostic performance is to be optimized.