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Objective: To develop enhanced prediction models to update the QUiPP App prototype, a tool providing individualized risk of spontaneous preterm birth (sPTB), for use in women with symptoms of threatened preterm labor (TPTL), incorporating risk factors, transvaginal ultrasound assessment of cervical length (CL) and cervicovaginal fluid quantitative fetal fibronectin (qfFN) test results.Methods: Participants were pregnant women between 23 + 0 and 34 + 6 weeks' gestation with symptoms of TPTL, recruited as part of four prospective cohort studies carried out at 16 UK hospitals between October 2010 and October 2017. The training set comprised all women whose outcomes were known in May 2017 (n = 1032). The validation set comprised women whose outcomes were gathered between June 2017 and March 2018 (n = 506). Parametric survival models were developed for three combinations of predictors: risk factors plus qfFN test results alone, risk factors plus CL alone, and risk factors plus both qfFN and CL. The best models were selected using the Akaike and Bayesian information criteria. The estimated probability of sPTB < 30, < 34 or < 37 weeks' gestation and within 1 or 2 weeks of testing was calculated and receiver-operating-characteristics (ROC) curves were created to demonstrate the diagnostic ability of the prediction models.Results: Predictive statistics were similar between the training and the validation sets at most outcome time points and for each combination of predictors. Areas under the ROC curves (AUC) demonstrated that all three algorithms had good accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1 and 2 weeks' post-testing in the validation set, particularly the model combining risk factors plus qfFN alone (AUC: 0.96 at < 30 weeks; 0.85 at < 34 weeks; 0.77 at < 37 weeks; 0.91 at < 1 week from testing; and 0.92 at < 2 weeks from testing).Conclusions: Validation of the new prediction models suggests that the QUiPP App v.2 can reliably calculate risk of sPTB in women with TPTL. Use of the QUiPP App in practice could lead to better targeting of intervention, while providing reassurance and avoiding unnecessary intervention in women at low risk. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Accurate mid-pregnancy prediction of spontaneous preterm birth (sPTB) is essential to ensure appropriate surveillance of high-risk women. Advancing the QUiPP App prototype, QUiPP App v.2 aimed to provide individualized risk of delivery based on cervical length (CL), quantitative fetal fibronectin (qfFN) or both tests combined, taking into account further risk factors, such as multiple pregnancy. Here we report development of the QUiPP App v.2 predictive models for use in asymptomatic high-risk women, and validation using a distinct dataset in order to confirm the accuracy and transportability of the QUiPP App, overall and within specific clinically relevant time frames.Methods: This was a prospective secondary analysis of data of asymptomatic women at high risk of sPTB recruited in 13 UK preterm birth clinics. Women were offered longitudinal qfFN testing every 2-4 weeks and/or transvaginal ultrasound CL measurement between 18 + 0 and 36 + 6 weeks' gestation. A total of 1803 women (3878 visits) were included in the training set and 904 women (1400 visits) in the validation set. Prediction models were created based on the training set for use in three groups: patients with risk factors for sPTB and CL measurement alone, with risk factors for sPTB and qfFN measurement alone, and those with risk factors for sPTB and both CL and qfFN measurements. Survival analysis was used to identify the significant predictors of sPTB, and parametric structures for survival models were compared and the best selected. The estimated overall probability of delivery before six clinically important time points (< 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks after testing) was calculated for each woman and analyzed as a predictive test for the actual occurrence of each event. This allowed receiver-operating-characteristics curves to be plotted, and areas under the curve (AUC) to be calculated. Calibration was performed to measure the agreement between expected and observed outcomes.Results: All three algorithms demonstrated high accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks of testing, with AUCs between 0.75 and 0.90 for the use of qfFN and CL combined, between 0.68 and 0.90 for qfFN alone, and between 0.71 and 0.87 for CL alone. The differences between the three algorithms were not statistically significant. Calibration confirmed no significant differences between expected and observed rates of sPTB within 4 weeks and a slight overestimation of risk with the use of CL measurement between 22 + 0 and 25 + 6 weeks' gestation.Conclusions: The QUiPP App v.2 is a highly accurate prediction tool for sPTB that is based on a unique combination of biomarkers, symptoms and statistical algorithms. It can be used reliably in the context of communicating to patients the risk of sPTB. Whilst further work is required to determine its role in identifying women requiring prophylactic interventions, it is a reliable and convenient screening tool for planning follow-up or hospitalization for high-risk women. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: The M6 risk-prediction model was published as part of a two-step protocol using an initial progesterone level of ≤ 2 nmol/L to identify probable failing pregnancies (Step 1) followed by the M6 model (Step 2). The M6 model has been shown to have good triage performance for stratifying women with a pregnancy of unknown location (PUL) as being at low or high risk of harboring an ectopic pregnancy (EP). This study validated the triage performance of the two-step protocol in clinical practice by evaluating the number of protocol-related adverse events and how effectively patients were triaged.Methods: This was a prospective multicenter interventional study of 3272 women with a PUL, carried out between January 2015 and January 2017 in four district general hospitals and four university teaching hospitals in the UK. The final pregnancy outcome was defined as: a failed PUL (FPUL), an intrauterine pregnancy (IUP) or an EP (including persistent PUL (PPUL)). FPUL and IUP were grouped as low-risk and EP/PPUL as high-risk PUL. Serum progesterone and human chorionic gonadotropin (hCG) levels were measured at presentation in all patients. If the initial progesterone level was ≤ 2 nmol/L, patients were discharged and were asked to have a follow-up urine pregnancy test in 2 weeks to confirm a negative result. If the progesterone level was > 2 nmol/L or a measurement had not been taken, hCG level was measured again at 48 h and results were entered into the M6 model. Patients were managed according to the outcome predicted by the protocol. Those classified as 'low risk, probable FPUL' were advised to perform a urine pregnancy test in 2 weeks and those classified as 'low risk, probable IUP' were invited for a scan a week later. When a woman with a PUL was classified as high risk (i.e. risk of EP ≥ 5%) she was reviewed clinically within 48 h. One center used a progesterone cut-off of ≤ 10 nmol/L and its data were analyzed separately. If the recommended management protocol was not adhered to, this was recorded as a protocol deviation and classified as: unscheduled visit for clinician reason, unscheduled visit for patient reason or incorrect timing of blood test or ultrasound scan. The classifications outlined in the UK Good Clinical Practice (GCP) guidelines were used to evaluate the incidence of adverse events. Data were analyzed using descriptive statistics.Results: Of the 3272 women with a PUL, 2625 were included in the final analysis (317 met the exclusion criteria or were lost to follow-up, while 330 were evaluated using a progesterone cut-off of ≤ 10 nmol/L). Initial progesterone results were available for 2392 (91.1%) patients. In Step 1, 407 (15.5%) patients were classified as low risk (progesterone ≤ 2 nmol/L), of whom seven (1.7%) were ultimately diagnosed with an EP. In 279 of the remaining 2218 women with a PUL, the M6 model was not applied owing to protocol deviation or because the outcome was already known (usually on the basis of an ultrasound scan) before a second hCG reading was taken; of these patients, 30 were diagnosed with an EP. In Step 2, 1038 women with a PUL were classified as low risk, of whom eight (0.8%) had a final outcome of EP. Of 901 women classified as high risk at Step 2, 275 (30.5%) had an EP. Therefore, 275/320 (85.9%) EPs were correctly classified as high risk. Overall, 1445/2625 PUL (55.0%) were classified as low risk, of which 15 (1.0%) were EP. None of these cases resulted in a ruptured EP or significant clinical harm. Sixty-two women participating in the study had an adverse event, but no woman had a serious adverse event as defined in the UK GCP guidelines.Conclusions: This study has shown that the two-step protocol incorporating the M6 model effectively triaged the majority of women with a PUL as being at low risk of an EP, minimizing the follow-up required for these patients after just two visits. There were few misclassified EPs and none of these women came to significant clinical harm or suffered a serious adverse clinical event. The two-step protocol incorporating the M6 model is an effective and clinically safe way of rationalizing the management of women with a PUL. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13, contingent on the results of the first-trimester combined test in twin pregnancy.Methods: Screening for trisomies 21, 18 and 13 was carried out in 959 twin pregnancies by assessment of a combination of maternal age, fetal nuchal translucency thickness, and serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-13 weeks' gestation in two UK NHS hospitals. Women in the high-risk group (risk ≥ 1 in 100) were offered the option of invasive testing, cfDNA testing or no further testing, and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates.Results: In 42 (4.4%) of the 959 pregnancies, there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow-up. The 917 pregnancies with known trisomic status of both twins included six that were discordant for trisomy 21, four that were discordant for trisomy 18 and 907 with no trisomy 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.1%) and 667 (72.7%) of the pregnancies were classified as high risk, intermediate risk and low risk, respectively. The high-risk group included five (83.3%) cases of trisomy 21 and three (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included six pregnancies with trisomy 21, three with trisomy 18 and 206 with no trisomy 21, 18 or 13. The cfDNA test classified correctly as screen positive all six cases of trisomy 21 and two of the three with trisomy 18, and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening led to prenatal detection of all cases of trisomy 21 and three of four with trisomy 18.Conclusion: This study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency anaemia is a common problem in pregnancy despite national recommendations and guidelines for treatment. The aim of this study was to appraise the evidence against the UK National Screening Committee (UKNSC) criteria as to whether a national screening programme could reduce the prevalence of iron deficiency anaemia and/or iron deficiency in pregnancy and improve maternal and fetal outcomes.Methods: Search strategies were developed for the Cochrane library, Medline and Embase to identify evidence relevant to UK National Screening Committee (UKNSC) appraisal criteria which cover the natural history of iron deficiency and iron deficiency anaemia, the tests for screening, clinical management and evidence of cost effectiveness.Results: Many studies evaluated haematological outcomes of anaemia, but few analysed clinical consequences. Haemoglobin and ferritin appeared the most suitable screening tests, although future options may follow recent advances in understanding iron homeostasis. The clinical consequences of iron deficiency without anaemia are unknown. Oral and intravenous iron are effective in improving haemoglobin and iron parameters. There have been no trials or economic evaluations of a national screening programme for iron deficiency anaemia in pregnancy.Conclusions: Iron deficiency in pregnancy remains an important problem although effective tests and treatment exist. A national screening programme could be of value for early detection and intervention. However, high quality studies are required to confirm whether this would reduce maternal and infant morbidity and be cost effective. [ABSTRACT FROM AUTHOR]