There is an ongoing debate about the possible influences of nonnutritive sweeteners (NNS) on body weight. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) with NNS to assess their impact on body weight. We systematically searched for RCTs at least 4 weeks in duration, evaluating the effect of NNS on body weight, both in subjects with healthy weight and in subjects with overweight/obesity at any age, and compared the effects of NNS vs caloric and noncaloric comparators. The primary outcome was the difference in body weight between NNS and comparators. Twenty studies were eligible (n = 2914). Participants consuming NNS showed significant weight/BMI differences favouring NNS compared with nonusers. Grouping by nature of comparator revealed that NNS vs placebo/no intervention and NNS vs water produced no effect. When comparing NNS vs sucrose, significant weight/BMI differences appeared favouring NNS. Consumption of NNS led to significantly negative weight/BMI differences in unrestricted energy diets, but not in weight-reduction diets. Participants with overweight/obesity and adults showed significant favourable weight/BMI differences with NNS. Data suggest that replacing sugar with NNS leads to weight reduction, particularly in participants with overweight/obesity under an unrestricted diet, information that could be utilized for evidence-based public policy decisions. K E Y W O R D S artificial sweeteners, body weight, obesity, systematic review

STUDY QUESTION Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)? SUMMARY ANSWER Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management. WHAT IS KNOWN ALREADY Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing. STUDY DESIGN, SIZE, DURATION This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S) Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina’s Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.

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CONTRIBUTION What are the novel findings of this work?This study provides evidence of a higher risk of adverse outcome in suspected third-trimester small-forgestational-age (SGA) fetuses with abnormal uterine artery Doppler, which is comparable to that in late SGA fetuses with abnormal cerebroplacental ratio. What are the clinical implications of this work?The findings from this study should enable clinicians to assess the risk of adverse perinatal outcome in SGA fetuses, using the likelihood ratios of abnormal third-trimester uterine artery Doppler to calculate the posterior probability, using an evidence-based approach. ABSTRACTObjective To investigate the predictive ability for adverse perinatal outcome of abnormal third-trimester uterine artery Doppler in late small-for-gestational-age (SGA) fetuses.Methods A systematic search was performed to identify relevant observational studies and randomized controlled trials evaluating the performance of abnormal third-trimester uterine artery Doppler for the prediction of adverse perinatal outcome in suspected SGA fetuses and SGA neonates. Abnormal uterine artery Doppler was defined as uterine artery pulsatility index > 95 th percentile or ≥ 2 SD above the mean, or bilateral uterine artery notching. Hierarchical summary receiver-operating-characteristics (ROC) curves were con-structed using random-effects modeling. Bayesian analysis was used to calculate the posterior probability of adverse perinatal outcome following an abnormal or normal uterine artery Doppler assessment.Results Seventeen observational studies (including 7552 fetuses either diagnosed with suspected SGA (n = 3461) or later diagnosed as a SGA neonate (n = 4091)) met the inclusion criteria; no randomized-controlled trials met the inclusion criteria. Summary ROC curves showed that, among suspected SGA fetuses, the best predictive accuracy of abnormal third-trimester uterine artery Doppler was for perinatal mortality and the worst was for composite adverse perinatal outcome, with areas under the summary ROC curves of 0.90 and 0.66, respectively. The corresponding positive and negative likelihood ratios were 16.5 and 0.6 for perinatal mortality and 2.82 and 0.65 for composite adverse perinatal outcome, respectively. Following an abnormal vs normal uterine artery Doppler assessment, the posterior risks for composite adverse perinatal outcome, admission to the neonatal intensive care unit, Cesarean section for intrapartum fetal compromise, 5-min Apgar score < 7, neonatal acidosis and perinatal death were: 52.3% vs 20.2%, 48.6% vs 18.7%, 23.1% vs 15.2%, 3.59% vs 1.32%, 9.15% vs 5.12% and 31.4% vs 1.64%, respectively.Conclusion Abnormal uterine artery Doppler in the third trimester appears to be moderately useful in predicting perinatal death in pregnancies with suspected SGA.

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Objective In addition to the lungs, the placenta and the endothelium can be affected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) are markers of endothelial dysfunction and could potentially serve as predictors of severe coronavirus disease 2019 (COVID‐19). We aimed to investigate the association of serum concentrations of sFlt‐1 and PlGF with the severity of COVID‐19 in pregnancy. Methods This was a prospective cohort study carried out in a tertiary care hospital in Mexico City, Mexico. Symptomatic pregnant women with a positive reverse‐transcription quantitative polymerase chain reaction test for SARS‐CoV‐2 infection who fulfilled the criteria for hospitalization were included. The primary outcome was severe pneumonia due to COVID‐19. Secondary outcomes were intensive care unit (ICU) admission, viral sepsis and maternal death. sFlt‐1 levels were expressed as multiples of the median (MoM). The association between sFlt‐1 and each adverse outcome was explored by logistic regression analysis, adjusted for gestational age for outcomes occurring in more than five patients, and the predictive performance was assessed by receiver‐operating‐characteristics‐curve analysis. Results Among 113 pregnant women with COVID‐19, higher sFlt‐1 MoM was associated with an increased probability of severe pneumonia (adjusted odds ratio (aOR), 1.817 (95% CI, 1.365–2.418)), ICU admission (aOR, 2.195 (95% CI, 1.582–3.047)), viral sepsis (aOR, 2.318 (95% CI, 1.407–3.820)) and maternal death (unadjusted OR, 5.504 (95% CI, 1.079–28.076)). At a 10% false‐positive rate, sFlt‐1 MoM had detection rates of 45.2%, 66.7%, 83.3% and 100% for severe COVID‐19 pneumonia, ICU admission, viral sepsis and maternal death, respectively. PlGF values were similar between women with severe and those with non‐severe COVID‐19 pneumonia. Conclusion sFlt‐1 MoM is higher in pregnant women with severe COVID‐19 and has the capability to predict serious adverse pregnancy events, such as severe pneumonia, ICU admission, viral sepsis and maternal death. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background: Preterm birth causes an increased risk for perinatal morbidity and mortality.Objective: To determine whether mid-trimester 17-alpha-hydroxyprogesterone caproate (17-OHPC) reduces the risk of recurrent preterm birth and adverse perinatal outcomes.Search strategy: Systematic search to identify relevant studies published in different languages, registered after 2000, using appropriate MeSH terms.Selection criteria: Inclusion criteria were women between 16 and 26 +6 weeks of pregnancy with history of preterm delivery in any pregnancy randomized to either 17-OHPC or placebo/no treatment. Data collection and analysis:The number of preterm births and adverse outcomes in the 17-OHPC and placebo arms over the total number of patients in each randomized group were used to calculate the risk ratio (RR) by random-effects models using the Mantel-Haenszel method. Between-study heterogeneity was assessed using tau 2 , χ 2 (Cochrane Q), and I 2 statistics.Main results: Four studies were included. There was a 29% (RR 0.71; 95% CI, 0.53-0.96; P=0.001), 26% (RR 0.74; 95% CI, 0.58-0.96; P=0.021), and 40% (RR 0.60; 95% CI, 0.42-0.85; P=0.004) reduction in recurrent preterm birth at <37, <35, and <32 weeks, respectively, in the 17-OHPC group compared with placebo. The reduction in neonatal death was 68% (RR 0.32; 95% CI, 0.15-0.66; P=0.002).Conclusions: 17-OHPC could reduce the risk of recurrent preterm birth at <37, <35, and <28 weeks and neonatal death. PROSPERO: CDR42017082190 K E Y W O R D S 17-alpha-hydroxyprogesterone caproate; Intramuscular progesterone; Meta-analysis; Preterm birth; Recurrent preterm birth; Systematic review | 157 Fernandez-Macias eT aL. −− 100.0% −− −− 69.0% 31.0% 35.3% 13.0% 20.8% 31.0% Weight | 163 Fernandez-Macias eT aL.

Objective To assess the added value of chromosomal microarray analysis (CMA) over conventional karyotyping to assess the genetic causes in stillbirth. Methods To identify relevant studies, published in English or Spanish and without publication time restrictions, we performed a systematic search of PubMed, SCOPUS and ISI Web of Science databases, The Cochrane Library and the PROSPERO register of systematic reviews, for case series of fetal loss ≥ 20 weeks of gestation, with normal or suspected normal karyotype, undergoing CMA and with at least five subjects analyzed. To investigate quality, two reviewers evaluated independently the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. For the meta‐analysis, the incremental yield of CMA over karyotyping was assessed by single‐proportion analysis using a random‐effects model (weighting by inverse variance). We assessed heterogeneity between studies and performed a sensitivity analysis and a subgroup analysis of structurally abnormal (malformed or growth‐restricted) and normal fetuses. Results Included in the meta‐analysis were seven studies involving 903 stillborn fetuses which had normal karyotype. The test success rate achieved by conventional cytogenetic analysis was 75%, while that for CMA was 90%. The incremental yield of CMA over conventional karyotyping based on the random‐effects model was 4% (95% CI, 3–5%) for pathogenic copy‐number variants (pCNVs) and 8% (95% CI, 4–17%) for variants of unknown significance. Subgroup analysis showed a 6% (95% CI, 4–10%) incremental yield of CMA for pCNVs in structurally abnormal fetuses and 3% (95% CI, 1–5%) incremental yield for those in structurally normal fetuses. The pCNV found most commonly was del22q11.21. Conclusions CMA, incorporated into the stillbirth work‐up, improves both the test success rate and the detection of genetic anomalies compared with conventional karyotyping. To achieve a genetic diagnosis in stillbirth is particularly relevant for the purpose of counseling regarding future pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.