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Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Objective: We have previously established that a logistic regression model, based on maternal demographic characteristics and blood pressure measured at 11–13 weeks' gestation, can identify about 70% of women who develop future chronic hypertension (CH) in the 3 years following pregnancy, at a screen‐positive rate of 10%. Furthermore, in midgestation, women who subsequently develop hypertensive disorders of pregnancy (HDP) have increased peripheral vascular resistance and mild cardiac functional and morphological alterations and these cardiovascular abnormalities persist for at least 2 years after delivery. In this study, we set out to examine whether use of the first‐trimester risk model for subsequent development of CH can help to identify women at high risk for cardiovascular maladaptation in midgestation. Methods: This was a prospective observational study of 3812 women with singleton pregnancy attending for a routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation and again at 19 + 1 to 23 + 3 weeks at King's College Hospital, London, UK, between December 2019 and August 2020. The first‐trimester visit included recording of maternal demographic characteristics and medical history and measurement of systolic and diastolic blood pressure. In midgestation, detailed maternal cardiovascular assessment was carried out. The association between risk for development of CH, determined from first‐trimester assessment, and cardiovascular indices in midgestation was examined. Results: Women who were at high risk for development of future CH, compared to those at low risk, had a higher incidence of HDP. In addition, high‐risk women had reduced systolic and diastolic function in midgestation. Among women with HDP, those who were at high risk for future CH, compared to those at low risk, had worse cardiac function in midgestation. Conclusions: Use of a model for first‐trimester prediction of subsequent development of CH can identify women who show evidence of cardiac maladaptation in midgestation. Further studies are needed to clarify whether women who screen as high risk for future CH, compared to those at low risk, have reduced cardiac function beyond pregnancy. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The first-trimester prediction of spontaneous preterm birth (sPTB) has been elusive, and current screening is heavily dependent on obstetric history. However, nullipara lack a relevant history and are at higher risk for spontaneous (s)PTB ≤ 32 weeks compared to multipara. No available objective first-trimester screening test has proven a fair predictor of sPTB ≤ 32 weeks. We questioned whether a panel of maternal plasma cell-free (PCF) RNAs (PSME2, NAMPT, APOA1, APOA4, and Hsa-Let-7g) previously validated at 16–20 weeks for the prediction of sPTB ≤ 32 weeks might be useful in first-trimester nullipara. Sixty (60) nulliparous women (40 with sPTB ≤ 32 weeks) who were free of comorbidities were randomly selected from the King’s College Fetal Medicine Research Institute biobank. Total PCF RNA was extracted and the expression of panel RNAs was quantitated by qRT-PCR. The analysis employed, primarily, multiple regression with the main outcome being the prediction of subsequent sPTB ≤ 32 weeks. The test performance was judged by the area under the curve (AUC) using a single threshold cut point with observed detection rates (DRs) at three fixed false positive rates (FPR). The mean gestation was 12.9 ± 0.5 weeks (range 12.0–14.1 weeks). Two RNAs were differentially expressed in women destined for sPTB ≤ 32 weeks: APOA1 (p < 0.001) and PSME2 (p = 0.05). APOA1 testing at 11–14 weeks predicted sPTB ≤ 32 weeks with fair to good accuracy. The best predictive model generated an AUC of 0.79 (95% CI 0.66–0.91) with observed DRs of 41%, 61%, and 79% for FPRs of 10%, 20%, and 30%, including crown–rump length, maternal weight, race, tobacco use, and age.

Objectives: First, to evaluate the predictive performance for preterm growth‐related neonatal morbidity of a high soluble fms‐like tyrosine kinase‐1 (sFlt‐1)/placental growth factor (PlGF) ratio or low PlGF at midgestation and, second, to compare the performance of a high sFlt‐1/PlGF ratio or low PlGF with that of the competing‐risks model for small‐for‐gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight and uterine artery pulsatility index. Methods: This was a prospective observational study in women attending for a routine hospital visit at 19–24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFlt‐1. The primary outcome was delivery < 32 and < 37 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt‐1/PlGF ratio > 90th percentile and the competing‐risks model for SGA were estimated and then compared using McNemar's test. Results: In the study population of 40 241 women, prediction of preterm growth‐related neonatal morbidity provided by the competing‐risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt‐1/PlGF ratio. For example, at a screen‐positive rate of 10.0%, as defined by the sFlt‐1/PlGF ratio > 90th percentile, the competing‐risks model predicted 70.1% (95% CI, 61.0–79.2%) of SGA < 10th percentile and 76.9% (95% CI, 67.6–86.3%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered < 32 weeks' gestation. The respective values for SGA with major neonatal morbidity were 73.8% (95% CI, 64.4–83.2%) and 77.9% (95% CI, 68.0–87.8%). These were significantly higher than the respective values of 35.1% (95% CI, 25.6–44.6%), 35.9% (95% CI, 25.3–46.5%), 38.1% (95% CI, 27.7–48.5%) and 39.7% (95% CI, 28.1–51.3%) achieved by the application of the sFlt‐1/PlGF ratio > 90th percentile (all P < 0.0001). Conclusion: At midgestation, the prediction of growth‐related neonatal morbidity by the competing‐risks model for SGA is superior to that of a high sFlt‐1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons. Methods: Gestational‐age‐ and chorionicity‐specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown–rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z‐scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins. Results: Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch‐up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50th percentile was at the 50th percentile of singleton pregnancies at 23 weeks, the 43rd percentile at 28 weeks, the 32nd percentile at 32 weeks and the 22nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50th percentile was at the 36th percentile of singleton pregnancies at 24 weeks, the 29th percentile at 28 weeks, the 19th percentile at 32 weeks and the 12th percentile at 36 weeks. Conclusions: In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in growth trajectories between twin and singleton pregnancies becomes more pronounced as gestational age increases. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objectives: First, to examine the predictive performance of maternal serum glycosylated fibronectin (GlyFn) at 35 + 0 to 36 + 6 weeks' gestation in screening for delivery with pre‐eclampsia (PE) and delivery with gestational hypertension (GH) at ≥ 37 weeks' gestation, both within 3 weeks and at any time after the examination. Second, to compare the predictive performance for delivery with PE and delivery with GH of various combinations of biomarkers, including GlyFn, mean arterial pressure (MAP), uterine artery pulsatility index (UtA‐PI), serum placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1). Third, to compare the predictive performance for delivery with PE and delivery with GH by serum PlGF concentration, sFlt‐1/PlGF concentration ratio and the competing‐risks model with different combinations of biomarkers as above. Fourth, to compare the predictive performance of screening at 11 + 0 to 13 + 6 weeks vs 35 + 0 to 36 + 6 weeks for delivery with PE and delivery with GH at ≥ 37 weeks' gestation. Methods: This was a case–control study in which maternal serum GlyFn was measured in stored samples from a non‐intervention screening study in singleton pregnancies at 35 + 0 to 36 + 6 weeks' gestation using a point‐of‐care device. We used samples from women who delivered at ≥ 37 weeks' gestation, including 100 who developed PE, 100 who developed GH and 600 controls who did not develop PE or GH. In all cases, MAP, UtA‐PI, PlGF and sFlt‐1 were measured during the routine visit at 35 + 0 to 36 + 6 weeks. We used samples from patients that had been examined previously at 11 + 0 to 13 + 6 weeks' gestation. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements from the medical history. Similarly, the measured values of MAP, UtA‐PI, PlGF and sFlt‐1 were converted to MoM. The competing‐risks model was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal risk factors, with various combinations of biomarker MoM values to derive the patient‐specific risks of delivery with PE. The performance of screening of different strategies was estimated by examining the detection rate (DR) at a 10% fixed false‐positive rate (FPR) and McNemar's test was used to compare the DRs between the different methods of screening. Results: The DR, at 10% FPR, of screening by the triple test (maternal risk factors plus MAP, PlGF and sFlt‐1) was 83.7% (95% CI, 70.3–92.7%) for delivery with PE within 3 weeks of screening and 80.0% (95% CI, 70.8–87.3%) for delivery with PE at any time after screening, and this performance was not improved by the addition of GlyFn. The performance of screening by a combination of maternal risk factors, MAP, PlGF and GlyFn was similar to that of the triple test, both for delivery with PE within 3 weeks and at any time after screening. The performance of screening by a combination of maternal risk factors, MAP, UtA‐PI and GlyFn was similar to that of the triple test, and they were both superior to screening by low PlGF concentration (PE within 3 weeks: DR, 65.3% (95% CI, 50.4–78.3%); PE at any time: DR, 56.0% (95% CI, 45.7–65.9%)) or high sFlt‐1/PlGF concentration ratio (PE within 3 weeks: DR, 73.5% (95% CI, 58.9–85.1%); PE at any time: DR, 63.0% (95% CI, 52.8–72.4%)). The predictive performance of screening at 35 + 0 to 36 + 6 weeks' gestation for delivery with PE and delivery with GH at ≥ 37 weeks' gestation was by far superior to screening at 11 + 0 to 13 + 6 weeks. Conclusion: GlyFn is a potentially useful biomarker in third‐trimester screening for term PE and term GH, but the findings of this case–control study need to be validated by prospective screening studies. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Accurate identification of independent predictors of stillbirth is needed to define preventive strategies. We aim to examine the independent contribution of maternal race in the risk of stillbirth after adjusting for maternal characteristics and medical history. There are two components to the study: first, prospective screening in 168,966 women with singleton pregnancies coordinated by the Fetal Medicine Foundation (FMF) and second, a systematic review and meta-analysis of studies reporting on race and stillbirth. In the FMF study, logistic regression analysis found that in black women, the risk of stillbirth, after adjustment for confounders, was higher than in white women (odds ratio 1.78, 95% confidence interval 1.50 to 2.11). The risk for other racial groups was not significantly different. The literature search identified 20 studies that provided data on over 6,500,000 pregnancies, but only 10 studies provided risks adjusted for some maternal characteristics; consequently, the majority of these studies did not provide accurate contribution of different racial groups to the prediction of stillbirth. It is concluded that in women of black origin, the risk of stillbirth, after adjustment for confounders, is about twofold higher than in white women. Consequently, closer surveillance should be granted for these women.

Prenatal trisomy 21 (T21) screening commonly involves testing a maternal blood sample for fetal DNA aneuploidy. It is reliable but poses a cost barrier to universal screening. We hypothesized maternal plasma RNA screening might provide similar reliability but at a lower cost. Discovery experiments used plasma cell-free RNA from 20 women 11–13 weeks tested by RNA and miRNA microarrays followed by qRT-PCR. Thirty-six mRNAs and 18 small RNAs of the discovery cDNA were identified by qPCR as potential markers of embryonic T21. The second objective was validation of the RNA predictors in 998 independent pregnancies at 11–13 weeks including 50 T21. Initial analyses identified 9–15 differentially expressed RNA with modest predictive power (AUC < 0.70). The 54 RNAs were then subjected to machine learning. Eleven algorithms were trained on one partition and tested on an independent partition. The three best algorithms were identified by Kappa score and the effects of training/testing partition size and dataset class imbalance on prediction were evaluated. Six to ten RNAs predicted T21 with AUCs up to 1.00. The findings suggest that maternal plasma collected at 11–13 weeks, tested by qRT-PCR, and classified by machine learning, may accurately predict T21 for a lower cost than plasma DNA, thus opening the door to universal screening.

Introduction Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.Methods and analysis MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.Ethics and dissemination All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.

The exposure to environmental stress can trigger epigenetic variation, which may have several evolutionary consequences. Polyploidy seems to affect the DNA methylation profiles. Nevertheless, it abides unclear whether temperature stress can induce methylations changes in different cytotypes and to what extent a treatment shift is translated to an epigenetic response. A suitable model system for studying these questions is Ranunculus kuepferi, an alpine perennial herb. Diploid and autotetraploid individuals of R. kuepferi were exposed to cold (+7°C day/+2°C night; frost treatment −1°C cold shocks for 3 nights per week) and warm (+15° day/+10°C night) conditions in climate growth chambers for two consecutive flowering periods and shifted from one condition to the other after the first flowering period. Methylation-sensitive amplified fragment-length polymorphism markers were applied for both years, to track down possible alterations induced by the stress treatments. Patterns of methylation suggested that cytotypes differed significantly in their profiles, independent from year of treatment. Likewise, the treatment shift had an impact on both cytotypes, resulting in significantly less epiloci, regardless the shift's direction. The AMOVAs revealed higher variation within than among treatments in diploids. In tetraploids, internally-methylated loci had a higher variation among than within treatments, as a response to temperature's change in both directions, and support the hypothesis of temperature stress affecting the epigenetic variation. Results suggest that the temperature-sensitivity of DNA methylation patterns shows a highly dynamic phenotypic plasticity in R. kuepferi, as both cytotypes responded to temperature shifts. Furthermore, ploidy level, even without effects of hybridization, has an important effect on epigenetic background variation, which may be correlated with the DNA methylation dynamics during cold acclimation.

Alpine habitats are shaped by harsh abiotic conditions and cold climates. Temperature stress can affect phenotypic plasticity, reproduction, and epigenetic profiles, which may affect acclimation and adaptation. Distribution patterns suggest that polyploidy seems to be advantageous under cold conditions. Nevertheless, whether temperature stress can induce gene expression changes in different cytotypes, and how the response is initialized through gene set pathways and epigenetic control remain vague for non-model plants. The perennial alpine plant Ranunculus kuepferi was used to investigate the effect of cold stress on gene expression profiles. Diploid and autotetraploid individuals were exposed to cold and warm conditions in climate growth chambers and analyzed via transcriptome sequencing and qRT-PCR. Overall, cold stress changed gene expression profiles of both cytotypes and induced cold acclimation. Diploids changed more gene set pathways than tetraploids, and suppressed pathways involved in ion/cation homeostasis. Tetraploids mostly activated gene set pathways related to cell wall and plasma membrane. An epigenetic background for gene regulation in response to temperature conditions is indicated. Results suggest that perennial alpine plants can respond to temperature extremes via altered gene expression. Tetraploids are better acclimated to cold conditions, enabling them to colonize colder climatic areas in the Alps.

Small for gestational age (SGA) fetuses/neonates are characterized by the increased risk for adverse outcomes that can be reduced if the condition is identified antenatally. We have recently developed a new approach in SGA prediction that considers SGA a spectrum condition that is reflected in two dimensions: gestational age at delivery and Z score in birth weight for gestational age. The new method has a better predictive ability than the traditionally used risk-scoring systems and logistic regression models. In this prospective study in 40241 singleton pregnancies, at 19–24 weeks’ gestation, we examined the potential value of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and the ratio of sFlt-1 to the angiogenic placental growth factor (PlGF) in the prediction of SGA. We found that first, sFlt-1 did not improve the performance of screening by maternal risk factors, and second, the ratio of sFlt-1/PlGF had a worse performance than PlGF alone in the prediction of SGA. Consequently, second trimester sFlt-1 and sFlt-1/PlGF are not useful in screening for SGA.

We previously reported a logistic regression model for prediction of GDM from maternal characteristics and medical history in 75,161 singleton pregnancies. In this study of 1376 twin and 13,760 singleton pregnancies recruited at 11–13 weeks’ gestation, we extend the model to include terms for twin pregnancies. We found the respective odds of GDM in dichorionic and monochorionic twin pregnancies to be 1.36 (95% CI: 1.02–1.81) and 2.78 (95% CI: 1.72–4.48) times higher than in singleton pregnancies. In both singleton and twin pregnancies, the risk for GDM increased with maternal age and weight and birth weight z-score of a baby in a previous pregnancy and is higher in women with a previous pregnancy complicated by GDM; in those with a first- or second-degree relative with diabetes mellitus; in women of Black, East Asian, and South Asian racial origin; and in pregnancies conceived through the use of ovulation-induction drugs. In singleton pregnancies, at 10% and 20% false-positive rate, the detection rate was 43% and 58%, respectively. In twin pregnancies, using risk cut-offs corresponding to 10% and 20% false-positive rates in singletons, the respective false-positive rates were 27% and 47%, and the detection rates were 63% and 81%.

Objective: To compare the predictive performance for delivery with pre‐eclampsia (PE) within 2 weeks of assessment in women with chronic hypertension at 24–41 weeks' gestation between serum glycosylated fibronectin (GlyFn) concentration, serum placental growth factor (PlGF) concentration and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) to PlGF concentration ratio. Methods: This was a prospective study of 104 women with a singleton pregnancy and chronic hypertension presenting at 24–41 weeks' gestation. Twenty‐six (25.0%) cases developed superimposed PE within 2 weeks of sampling. We compared the predictive performance for superimposed PE between GlyFn, PlGF and the sFlt‐1/PlGF ratio at a fixed screen‐positive rate of approximately 10%. Results: The median gestational age at sampling was 34.1 (interquartile range, 31.5–35.6) weeks and 84.6% (88/104) of cases were sampled at < 36 weeks. The predictive performance for superimposed PE of the three methods of screening was similar, with detection rates of about 23–27%, at a screen‐positive rate of 11% and a false‐positive rate of about 5%. Conclusions: Measurement of GlyFn is a simple point‐of‐care test that can be carried out without need for a laboratory and provide results within 10 min of testing. In this respect, it could potentially replace the angiogenic markers that are used currently in the prediction of imminent PE in high‐risk women. However, neither GlyFn nor angiogenic factors are likely to improve the management of women with chronic hypertension because their predictive performance for superimposed PE is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]