Prediction and prevention of preterm birth: Quality assessment and systematic review of clinical practice guidelines using the AGREE II framework.

BACKGROUND: Prediction of pregnancies at risk of preterm birth (PTB) may allow targeted prevention strategies. OBJECTIVES: To assess quality of clinical practice guidelines (CPGs) and identify areas of agreement and contention in prediction and prevention of spontaneous PTB. SEARCH STRATEGY: We searched for CPGs regarding PTB prediction and prevention in asymptomatic singleton pregnancies without language restriction in January 2024. SELECTION CRITERIA: CPGs included were published between July 2017 and December 2023 and contained statements intended to direct clinical practice. DATA COLLECTION AND ANALYSIS: CPG quality was assessed using the AGREE-II tool. Recommendations were extracted and grouped under domains of prediction and prevention, in general populations and high-risk groups. MAIN RESULTS: We included 37 CPGs from 20 organizations; all were of moderate or high quality overall. There was consensus in prediction of PTB by identification of risk factors and cervical length screening in high-risk pregnancies and prevention of PTB by universal screening and treatment for asymptomatic bacteriuria, screening and treatment for BV in high-risk pregnancies, and use of preventative progesterone and cerclage. Areas of contention or limited consensus were the role of PTB clinics, universal cervical length measurement, biomarkers and cervical pessaries. CONCLUSIONS: This review identified strengths and limitations of current PTB CPGs, and areas for future research.

Development of a semi-automated tool to measure fetal abdominal wall thickness during ultrasound at 20 weeks' gestation.

OBJECTIVES: To develop a semi-automated tool for measuring fetal abdominal wall thickness (AWT). To validate the software using images captured by other centers and create a nomogram for fetal AWT between 18 and 20 weeks. METHODS: A semiautomated tool that measured AWT was developed using images captured at the routine 20-week morphology scan. The software was developed using digital images captured routinely during scans of low-risk women. Inter- and intraobserver reliability was assessed between manual and semi-automated measures. The tool was validated using images acquired from other centers. Linear regression and quadratic polynomials were used to create a nomogram for AWT. RESULTS: The semi-automated tool was able to measure AWT in all images. Interoperator reliability was 0.90 and 0.97 (P < 0.05) for manual and semi-automated methods, respectively. Measurement agreement varied between three operators from moderate to excellent (0.77, 0.87, 0.92), with overall agreement being good (0.85). The tool could be successfully applied to 89% of images from other centers. A nomogram was generated for AWT measurements of fetuses at 18-20 weeks in normal, low risk mothers. CONCLUSION: Semi-automated measurement of AWT was feasible using images captured during the routine 20-week scan. This approach had lower inter- and intraobserver variability compared to manual measurement.

The Role of cfDNA Biomarkers and Patient Data in the Early Prediction of Preeclampsia: Artificial Intelligence Model.

OBJECTIVE: Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks' gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). METHODS: This secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the 'reference' classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units. RESULTS: Of 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks' gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0). CONCLUSION: Routinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

Impact of high-risk prenatal screening results for 22q11.2 deletion syndrome on obstetric and neonatal management: Secondary analysis from the SMART study.

OBJECTIVE: One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high-risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. METHODS: This was a secondary analysis from the SMART study. Patients with high-risk cfDNA results for 22q11.2DS were compared with the low-risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high-risk neonates without prenatal genetic confirmation with a 1:1 matched low-risk cohort. RESULTS: Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high-risk and 17,982 (99.79%) were low-risk for 22q11.2DS by cfDNA screening. High-risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal echocardiography (76.9%; 10/13 vs. 19.6%; 10/51, p < 0.001). High-risk newborns without prenatal diagnostic testing had higher rates of neonatal genetic testing (46.2%; 6/13 vs. 0%; 0/51, P < 0.001), echocardiography (30.8%; 4/13 vs. 4.0%; 2/50, p = 0.013), evaluation of calcium levels (46.2%; 6/13 vs. 4.1%; 2/49, P < 0.001) and lymphocyte count (53.8%; 7/13 vs. 15.7%; 8/51, p = 0.008). CONCLUSIONS: High-risk screening results for 22q11.2DS were associated with higher rates of prenatal and neonatal diagnostic genetic testing and other 22q11.2DS-specific evaluations. However, these interventions were not universally performed, and >50% of high-risk infants were discharged without genetic testing, representing possible missed opportunities to improve outcomes for affected individuals.

Do first-trimester screening algorithms for preeclampsia aligned to use of preventative therapies reduce the prevalence of pre-term preeclampsia: A systematic review and meta-analysis.

OBJECTIVE: Traditional obstetric practice relies upon history-based assessment to screen for preeclampsia and guide preventative therapies but is hampered by low sensitivity, high false-positive rates and low treatment rates. First-trimester screening algorithms represent the most efficacious approach for risk prediction and could target early initiation of aspirin to well-defined high-risk populations. A large randomised controlled trial has demonstrated the clinical benefits of this approach, but widespread practice implementation has remained elusive. METHODS: We performed a systematic review and meta-analysis summarising studies linking first-trimester preeclampsia screening algorithms with the initiation of preventative therapy and examined their effect on pre-term preeclampsia rates compared with standard maternity care. Odds ratios were calculated together with 95% confidence intervals. RESULTS: 7 studies with a total of 377,790 participants were included. Within singleton populations, early initiation of aspirin in response to a high-risk screening algorithm result reduced the prevalence of pre-term preeclampsia by 39% compared with routine antenatal care (odds ratio 0.61; 95% CI: 0.52-0.70). There were significant reductions in the prevalence of preeclampsia at <32-34 weeks, preeclampsia at any gestation and stillbirth. CONCLUSION: First-trimester screening algorithms for preeclampsia aligned with early initiation of preventative therapy with aspirin reduce the prevalence of pre-term preeclampsia.

Performance of prenatal cfDNA screening for sex chromosomes.

PURPOSE: The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation. METHODS: This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies. RESULTS: A total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and 14,486 pregnancies, respectively. Sensitivity, specificity, and positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%. CONCLUSION: Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, whereas the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.

Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results.

BACKGROUND: The clinical implications of nonreportable cell-free DNA screening results are uncertain, but such results may indicate poor placental implantation in some cases and be associated with adverse obstetrical and perinatal outcomes. OBJECTIVE: This study aimed to assess the outcomes of pregnancies with nonreportable cell-free DNA screening in a cohort of patients with complete genetic and obstetrical outcomes. STUDY DESIGN: This was a prespecified secondary analysis of a multicenter prospective observational study of prenatal cell-free DNA screening for fetal aneuploidy and 22q11.2 deletion syndrome. Participants who underwent cell-free DNA screening from April 2015 through January 2019 were offered participation. Obstetrical outcomes and neonatal genetic testing results were collected from 21 primary-care and referral centers in the United States, Europe, and Australia. The primary outcome was risk for adverse obstetrical and perinatal outcomes (aneuploidy, preterm birth at <28, <34, and <37 weeks' gestation, preeclampsia, small for gestational age or birthweight <10th percentile for gestational week, and a composite outcome that included preterm birth at <37 weeks, preeclampsia, small for gestational age, and stillbirth at >20 weeks) after nonreportable cell-free DNA screening because of low fetal fraction or other causes. Multivariable analyses were performed, adjusting for variables known to be associated with obstetrical and perinatal outcomes, nonreportable results, or fetal fraction. RESULTS: In total, 25,199 pregnant individuals were screened, and 20,194 were enrolled. Genetic confirmation was missing in 1165 (5.8%), 1085 (5.4%) were lost to follow-up, and 93 (0.5%) withdrew; the final study cohort included 17,851 (88.4%) participants who had cell-free DNA, fetal or newborn genetic confirmatory testing, and obstetrical and perinatal outcomes collected. Results were nonreportable in 602 (3.4%) participants. A sample was redrawn and testing attempted again in 427; in 112 (26.2%) participants, results were again nonreportable. Nonreportable results were associated with higher body mass index, chronic hypertension, later gestational age, lower fetal fraction, and Black race. Trisomy 13, 18, or 21 was confirmed in 1.6% with nonreportable tests vs 0.7% with reported results (P=.013). Rates of preterm birth at <28, 34, and 37 weeks, preeclampsia, and the composite outcome were higher among participants with nonreportable results, and further increased among those with a second nonreportable test, whereas the rate of small for gestational age infants was not increased. After adjustment for confounders, the adjusted odds ratios were 2.2 (95% confidence interval, 1.1-4.4) and 2.6 (95% confidence interval, 0.6-10.8) for aneuploidy, and 1.5 (95% confidence interval, 1.2-1.8) and 2.1 (95% confidence interval, 1.4-3.2) for the composite outcome after a first and second nonreportable test, respectively. Of the patients with nonreportable tests, 94.9% had a live birth, as opposed to 98.8% of those with reported test results (adjusted odds ratio for livebirth, 0.20 [95% confidence interval, 0.13-0.30]). CONCLUSION: Patients with nonreportable cell-free DNA results are at increased risk for a number of adverse outcomes, including aneuploidy, preeclampsia, and preterm birth. They should be offered diagnostic genetic testing, and clinicians should be aware of the increased risk of pregnancy complications.

First-trimester prediction of preterm prelabour rupture of membranes incorporating cervical length measurement.

OBJECTIVES: To examine early pregnancy risk factors for preterm prelabour rupture of membranes (PPROM) and develop a predictive model. STUDY DESIGN: Retrospective analysis of a cohort of mixed-risk singleton pregnancies screened in the first and second trimesters in three Danish tertiary fetal medicine centres, including a cervical length measurement at 11-14 weeks, at 19-21 weeks and at 23-24 weeks of gestation. Univariable and multivariable logistic regression analyses were employed to identify predictive maternal characteristics, biochemical and sonographic factors. Receiver operating characteristic (ROC) curve analysis was used to determine predictors for the most accurate model. RESULTS: Of 3477 screened women, 77 (2.2%) had PPROM. Maternal factors predictive of PPROM in univariable analysis were nulliparity (OR 2.0 (95% CI 1.2-3.3)), PAPP-A < 0.5 MoM (OR 2.6 (1.1-6.2)), previous preterm birth (OR 4.2 (1.9-8.9)), previous cervical conization (OR 3.6 (2.0-6.4)) and cervical length ≤ 25 mm on transvaginal imaging (first-trimester OR 15.9 (4.3-59.3)). These factors all remained statistically significant in a multivariable adjusted model with an AUC of 0.72 in the most discriminatory first-trimester model. The detection rate using this model would be approximately 30% at a false-positive rate of 10%. Potential predictors such as bleeding in early pregnancy and pre-existing diabetes mellitus affected very few cases and could not be formally assessed. CONCLUSIONS: Several maternal characteristics, placental biochemical and sonographic features are predictive of PPROM with moderate discrimination. Larger numbers are required to validate this algorithm and additional biomarkers, not currently used for first-trimester screening, may improve model performance.

Pre-eclampsia.

Pre-eclampsia is a life-threatening disease of pregnancy unique to humans and a leading cause of maternal and neonatal morbidity and mortality. Women who survive pre-eclampsia have reduced life expectancy, with increased risks of stroke, cardiovascular disease and diabetes, while babies from a pre-eclamptic pregnancy have increased risks of preterm birth, perinatal death and neurodevelopmental disability and cardiovascular and metabolic disease later in life. Pre-eclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension (>20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction or uteroplacental dysfunction. Pre-eclampsia is found only when a placenta is or was recently present and is classified as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia. The maternal syndrome of pre-eclampsia is driven by a dysfunctional placenta, which releases factors into maternal blood causing systemic inflammation and widespread maternal endothelial dysfunction. Available treatments target maternal hypertension and seizures, but the only 'cure' for pre-eclampsia is delivery of the dysfunctional placenta and baby, often prematurely. Despite decades of research, the aetiology of pre-eclampsia, particularly of term and postpartum pre-eclampsia, remains poorly defined. Significant advances have been made in the prediction and prevention of preterm pre-eclampsia, which is predicted in early pregnancy through combined screening and is prevented with daily low-dose aspirin, starting before 16 weeks of gestation. By contrast, the prediction of term and postpartum pre-eclampsia is limited and there are no preventive treatments. Future research must investigate the pathogenesis of pre-eclampsia, in particular of term and postpartum pre-eclampsia, and evaluate new prognostic tests and treatments in adequately powered clinical trials.

Interventions for the Prevention of Preterm Premature Rupture of Membranes: A Systematic Review and Meta-Analysis.

INTRODUCTION: Preterm prelabour rupture of membranes (PPRoM) is a significant cause of maternal and perinatal morbidity and mortality. The aim of this project was to identify interventions that reduce the prevalence of PPRoM. METHODS: Search strategy included a systematic literature search of MEDLINE, EMBASE, PubMed, and Cochrane Library. The selection criteria included randomized control studies that compared a therapy to standard care (no therapy or placebo) in pregnancy and included PPRoM as an outcome. Risk of bias was assessed according to the Cochrane risk-of-bias tool for randomized trials. Odds ratios with 95% confidence intervals were calculated using random-effects models. Quality of evidence was assessed using the GRADE methodology. RESULTS: Twenty-nine studies examining 10 interventions met the inclusion criteria. Therapies included docosahexaenoic acid (DHA), aspirin, rofecoxib, vitamin C alone and with vitamin E, folic acid (alone, with iron, with iron and zinc, within a multiple micronutrient supplement), zinc, calcium, copper, and treatment of bacterial vaginosis. There was no significant difference in the prevalence of PPRoM in the treatment groups compared to placebo, except for rofecoxib which showed an increased risk of PPRoM (RR 2.46, 95% CI 1.28-4.73; p = 0.007, 1 trial, 98 women; very low quality of evidence) and a multiple micronutrient supplement which showed a reduction in PPRoM (RR 0.40, 95% CI 0.19-0.84; p = 0.01, 1 trial, 1,671 women; very low quality of evidence). CONCLUSIONS: No interventions have been convincingly shown to reduce the prevalence of PPRoM. Given this is a common problem leading to significant morbidity and mortality, further research is required.

Shear wave elastography: the relationship of the cervical stiffness with gestational age and cervical length- a feasibility study.

OBJECTIVES: To standardize the measurement of shear wave elastography for assessment of cervical stiffness and its relationship with gestational age and cervical length. METHODS: A prospective cross-sectional study was conducted from September 2017 to March 2019. Data from 125 unselected women (at 11-13 + 6, 18-22 and 24-28 weeks' gestation) and 55 high-risk women were analyzed for the study. Six regions of interest were evaluated for cervical elastography in the mid-sagittal position by transvaginal ultrasound. Statistical analyses were performed using R statistical language in R-studio. Delivery outcomes were recorded for each patient. RESULTS: The shear wave elastography was feasible with good intraoperator and interoperator reproducibility. The endocervical canal and anterior lip internal position had the highest reproducibility (ICC-0.82, 0.75). Shear wave speed was significantly higher in all internal os regions than the external os. There was a statistically significant negative linear relationship of shear wave speed with the gestational age. There was a weak positive relationship between shear wave speed and cervical length. There was no difference between pregnancies with and without spontaneous preterm delivery in shear wave speed measurements and cervical length, although numbers were small for statistical analysis. The internal os of the large loop excision of the transformation zone group was stiffer than the normal population. CONCLUSION: Cervical elastography is feasible and effectively evaluates the tensile properties of the cervix during pregnancy. The most reproducible measurements were obtained at the anterior lip of the internal cervical os. Combining evaluation of cervical elasticity and length might further improve the identification of women at risk of preterm delivery. Currently, technical issues hinder the practical application of shear wave elastography in the clinical setting and require further research and development of the imaging modality.

Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.

BACKGROUND: Historically, prenatal screening has focused primarily on the detection of fetal aneuploidies. Cell-free DNA now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2 deletion syndrome, large cohort studies with confirmatory postnatal testing to assess test performance have not been reported. OBJECTIVE: This study aimed to assess the performance of single-nucleotide polymorphism-based, prenatal cell-free DNA screening for detection of 22q11.2 deletion syndrome. STUDY DESIGN: Patients who underwent single-nucleotide polymorphism-based prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are ≥500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome. RESULTS: Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524. In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% confidence interval, 42.8-94.5); specificity of 99.84% (95% confidence interval, 99.77-99.89); positive predictive value of 23.7% (95% confidence interval, 11.44-40.24), and negative predictive value of 99.98% (95% confidence interval, 99.95-100). None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome. The updated algorithm detected 10 of 12 cases (83.3%; 95% confidence interval, 51.6-97.9) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19; 95% confidence interval, 28.9-75.6). CONCLUSION: Noninvasive cell-free DNA prenatal screening for 22q11.2 deletion syndrome can detect most affected cases, including smaller nested deletions, with a low false positive rate.

Factors affecting cord blood leptin levels in a consecutive birth cohort.

INTRODUCTION: The fetus that fails to meet its ideal growth trajectory has increased risks of poor health outcomes throughout life. "Gold standard" methods of anthropometric assessment such as measurement of percentage body fat can be difficult to apply across populations and other biomarkers such as serum concentration of umbilical cord blood leptin may be more effective for screening. This study reports cord blood leptin levels in a large prospective consecutive birth cohort and assesses the relationship between leptin and neonatal and maternal factors. METHODS: Venous umbilical cord blood samples were collected from a prospective consecutive cohort of pregnancies at the time of delivery. Maternal and neonatal characteristics and details of delivery were collated. Serum leptin levels were measured, associations with demographic features were identified, and a normal range was established. The association between cord leptin level and neonatal outcome was tested. RESULTS: Umbilical cord leptin and maternal and neonatal characteristics were collected at 1275 births. The median leptin value was 10.8 ng/ml (IQR: 6.4, 17.8 ng/ml). Log10 leptin was significantly associated with gestation at delivery, birthweight (BWt), infant sex, plurality, and maternal body mass index (BMI) (p < .001). Observed leptin values were expressed as multiples of the median (MoM). The mean leptin MoM was significantly lower in infants admitted to NICU following delivery (0.85; 95% confidence interval [CI]: 0.78-0.91 versus 1.05; 95% CI: 1.03-1.06 (controls), p < .001). There was no significant association between leptin MoM values and 5-min Apgar scores. CONCLUSIONS: Neonatal cord leptin levels are influenced by a number of maternal and fetal characteristics. Absolute levels can be adjusted to account for normal population variation. Infants requiring admission to NICU have lower mean leptin MoM levels. Further studies are needed to see whether the identification of fetuses with polarized leptin levels (<5th or >95th centile) will benefit from further surveillance or intervention in infancy.

The use of vaginal progesterone as a maintenance therapy in women with arrested preterm labor: a double-blind placebo-randomized controlled trial.

BACKGROUND: The efficacy of maintenance tocolytic therapy after successful arrest of preterm labor remains controversial. The purpose of this study was to evaluate the efficacy of 400 mg of daily vaginal progesterone (cyclogest) after successful parenteral tocolysis to increase latency period and improvement of neonatal outcomes in women with threatened preterm labor. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, 85 participants were randomly allocated to either 400 mg daily of vaginal progesterone (n = 45) or placebo (n = 40) until 34 weeks of gestation. The primary outcomes were the time until delivery (latency period) and cervical length after 1 week of treatment. Secondary outcome were GA on delivery, type of delivery, incidence of low birth weight, perinatal morbidity and mortality. RESULTS: Longer mean latency until delivery (53.6 ± 16.8 versus 34.5 ± 12.9) days p = .0001; longer mean of gestational age on delivery (37.5 ± 2.2 versus 34.2 ± 2.1) weeks p = .0001; cervical length after 1 week of treatment (27.5 ± 5.5 versus 20.7 ± 3.1) mm p = .0001; low birth weight 12 (29.3%) versus 19 (57.6%) p = .01; and NICU admission 9 (22%) versus 15 (45.5%), were significantly different between the two groups. No significant differences were found between neonatal death 1 (2.4%) versus 2 (6.1%), p = .43; RDS 5 (12.2%) versus 8 (24.2%), p = .17; and need to mechanical ventilator 2 (5.4%) versus 6 (18.2%) p = .136, for the progesterone and placebo groups, respectively. CONCLUSION: Daily administration of 400 mg vaginal progesterone after successful parenteral tocolysis may increase latency preceding delivery and improves cervical shortening and neonatal outcome in women with preterm labor. Further confirmatory studies are warranted.

Maternal dietary fatty acid composition and newborn epigenetic aging-a geometric framework approach.

BACKGROUND: Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. OBJECTIVES: We sought to assess the collective impact of maternal dietary MUFAs, PUFAs, and SFAs on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. METHODS: Body fatness (n = 162), aortic intima-media thickness (aIMT; n = 131), heart rate variability (n = 118), and epigenetic age acceleration (n = 124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered FFQ. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. RESULTS: After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFAs, PUFAs, and SFAs (P = 0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFAs were positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFAs or PUFAs. We also demonstrate a potential beneficial association of omega-3 (n-3) PUFAs with newborn epigenetic age acceleration (P = 0.008). There was no significant association of fat class with newborn aIMT, heart rate variability, or body fatness. CONCLUSIONS: In this study, we demonstrated an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

Transverse position. Using rotation to aid normal birth-OUTcomes following manual rotation (the TURN-OUT trial): a randomized controlled trial.

BACKGROUND: The fetal occiput transverse position in the second stage of labor is associated with adverse maternal and perinatal outcomes. Prophylactic manual rotation in the second stage of labor is considered a safe and easy to perform procedure that has been used to prevent operative deliveries. OBJECTIVE: This study aimed to determine the efficacy of prophylactic manual rotation in the management of the occiput transverse position for preventing operative delivery. We hypothesized that among women who are at ≥37 weeks' gestation with a baby in the occiput transverse position early in the second stage of labor, manual rotation compared with a "sham" rotation will reduce the rate of operative delivery. STUDY DESIGN: A double-blinded, parallel, superiority, multicenter, randomized controlled clinical trial in 3 tertiary hospitals was conducted in Australia. The primary outcome was operative (cesarean, forceps, or vacuum) delivery. Secondary outcomes were cesarean delivery, serious maternal morbidity and mortality, and serious perinatal morbidity and mortality. Outcomes were analyzed by intention to treat. Proportions were compared using χ2 tests adjusted for stratification variables using the Mantel-Haenszel method or Fisher exact test. Planned subgroup analyses by operator experience and technique of manual rotation (digital or whole hand rotation) were performed. The planned sample size was 416 participants (trial registration: ACTRN12613000005752). RESULTS: Here, 160 women with a term pregnancy and a baby in the occiput transverse position in the second stage of labor, confirmed by ultrasound, were randomly assigned to receive either a prophylactic manual rotation (n=80) or a sham procedure (n=80), which was less than our original intended sample size. Operative delivery occurred in 41 of 80 women (51%) assigned to prophylactic manual rotation and 40 of 80 women (50%) assigned to a sham rotation (common risk difference, -4.2% [favors sham rotation]; 95% confidence interval, -21 to 13; P=.63). Among more experienced proceduralists, operative delivery occurred in 24 of 47 women (51%) assigned to manual rotation and 29 of 46 women (63%) assigned to a sham rotation (common risk difference, 11%; 95% confidence interval, -11 to 33; P=.33). Cesarean delivery occurred in 6 of 80 women (7.5%) in the manual rotation group and 7 of 80 women (8.7%) in the sham group. Instrumental (forceps or vacuum) delivery occurred in 35 of 80 women (44%) in the manual rotation group and 33 of 80 women (41%) in the sham group. There was no significant difference in the combined maternal and perinatal outcomes. The trial was terminated early because of limited resources. CONCLUSION: Planned prophylactic manual rotation did not result in fewer operative deliveries. More research is needed in the use of manual rotation from the occiput transverse position for preventing operative deliveries.

Attributable factors for the rising cesarean delivery rate over 3 decades: an observational cohort study.

BACKGROUND: Cesarean delivery rates continue to rise globally, the reasons for which are incompletely understood. OBJECTIVE: We aimed to characterize the attributable factors for the increasing cesarean delivery rates over a 30-year period within our health network. STUDY DESIGN: This was a planned observational cohort study across 2 hospitals (a large tertiary referral hospital and a metropolitan hospital) in Sydney, Australia using data from a previously published study. The following 2 time periods were compared: 1989-99 and 2009-16, between which the cesarean delivery rate increased from 19% to 30%. The participants were all women who had a cesarean delivery after 24 weeks' gestational age. The data were analyzed using multiple imputation and robust Poisson regression to calculate the differences in the adjusted and unadjusted relative risk of cesarean delivery and estimate the changes in the cesarean delivery rate attributable to maternal and clinical factors. The primary outcome was cesarean delivery. RESULTS: After 576 exclusions, 102,589 births were included in the analysis. Fifty-six percent of the increase in the rate of cesarean delivery was attributed to changes in the distribution of the maternal age, body mass index, and parity and to a history of previous cesarean delivery. An additional 10% of the increase was attributed to changes in the obstetrical management of the following high-risk pregnancies: multiple gestation, malpresentation (mainly breech), and preterm singleton birth. When prelabor cesarean deliveries for maternal choice, suspected fetal compromise, previous pregnancy issues, and suspected large fetus were excluded, 78% of the increase was attributed to either maternal factors or changes in the obstetrical management of these high-risk pregnancies. CONCLUSION: Most of the steep rise in the cesarean delivery rate from 19% to 30% was attributed to changes in the maternal demographic and clinical factors. This observation is relevant to developing preventative strategies that account for nulliparity, age, body mass index, and management of high-risk pregnancies.