Performance of cell-free DNA testing for common fetal trisomies in triplet pregnancies.

OBJECTIVE: In singleton pregnancies, the use of cell-free DNA (cfDNA) analysis as a screening test for common fetal trisomies has spread worldwide though we still lack sufficient data for its use in triplet pregnancies. The objective of this study is to assess the performance of cfDNA testing in detecting fetal aneuploidies in triplet pregnancies as a first-tier test. METHOD: We performed a retrospective cohort study including data from pregnant women with a triplet pregnancy who underwent cfDNA testing between May 1, 2017, and January 15, 2020. cfDNA was obtained by massive parallel sequencing (VeriSeq NIPT solution; Illumina®). The objectives of the study were to assess the diagnostic performance of cfDNA testing for trisomy 21 (T21) (primary outcome), trisomy 18 (T18) and 13 (secondary outcomes). RESULTS: During the study period, cfDNA testing was performed in 255 women with triplet pregnancy, of which 165 (64.7%) had a neonatal outcome available. Three tests were positive for T21, one of which was confirmed by an antenatal karyotype, and the other was confirmed at birth. The third case did not undergo an invasive procedure and was not confirmed at birth (false positive). In one case, cfDNA testing was positive for T18 and was confirmed by an antenatal karyotype. There were no cases of trisomy 13 in the cohort. The no-call rate was 2.4% at first sampling. Fifty-eight (22.7%) women had embryo reduction, which in 40 (69%) of whom was performed after the cfDNA test result. CONCLUSION: cfDNA testing could be offered as primary screening for main fetal aneuploidies in triplet pregnancies after provision of appropriate patient information.

The impact of preimplantation genetic testing for aneuploidy on prenatal screening.

OBJECTIVES: To determine whether preimplantation genetic testing for aneuploidy (PGT-A) is associated with a reduced risk of abnormal conventional prenatal screening results in singleton pregnancies conceived using in vitro fertilization (IVF). METHODS: This was a retrospective cohort study of singleton IVF pregnancies conceived from a single tertiary care center between January 2014 and September 2019. Exclusion criteria included mosaic embryo transfers, vanishing twin pregnancies, and cycles with missing outcome data. Two cases of prenatally diagnosed aneuploidy that resulted in early voluntary terminations were also excluded. The primary outcome of abnormal first or second-trimester combined screening results was compared between two groups: pregnancy conceived after transfer of a euploid embryo by PGT-A vs. transfer of an untested embryo. Multivariable backwards-stepwise logistic regression with Firth method was used to adjust for potential confounders. RESULTS: Of the 419 pregnancies included, 208 (49.6%) were conceived after transfer of a euploid embryo by PGT-A, and 211 (50.4%) were conceived after transfer of an untested embryo. PGT-A was not associated with a lower likelihood of abnormal first-trimester (adjusted OR 1.64, 95% CI 0.82-3.39) or second-trimester screening results (adjusted OR 0.96, 95% CI 0.56-1.64). The incidences of cell-free DNA testing, fetal sonographic abnormalities, genetic counseling, and invasive prenatal diagnostic testing were similar between the two groups. CONCLUSIONS: Our data suggest that PGT-A is not associated with a change in the likelihood of abnormal prenatal screening results or utilization of invasive prenatal diagnostic testing. Counseling this patient population regarding the importance of prenatal screening and prenatal diagnostic testing, where appropriate, remains essential.

Investigation on combined copy number variation sequencing and cytogenetic karyotyping for prenatal diagnosis.

BACKGROUND: We aimed to evaluate the clinical value of copy number variation-sequencing (CNV-Seq) in combination with cytogenetic karyotyping in prenatal diagnosis. METHODS: CNV-Seq and cytogenetic karyotyping were performed in parallel for 9452 prenatal samples for comparison of the diagnostic performance of the two methods, and to evaluate the screening performance of maternal age, maternal serum screening, fetal ultrasound scanning and noninvasive prenatal testing (NIPT) for fetal pathogenic copy number variation (CNV). RESULTS: Among the 9452 prenatal samples, traditional karyotyping detected 704 cases (7.5%) of abnormal cytogenetic karyotypes, 171 (1.8%) chromosome polymorphism, 20 (0.2%) subtle structural variations, 74 (0.7%) mutual translocation (possibly balanced), 52 (0.6%) without karyotyping results, and 8431 (89.2%) normal cytogenetic karyotypes. Among the 8705 cases with normal karyotype, polymorphism, mutual translocation, or marker chromosome, CNV-Seq detected 63 cases (0.7%) of pathogenic chromosome microdeletion/duplication. Retrospectively, noninvasive prenatal testing (NIPT) had high sensitivity and specificity for the screening of fetal pathogenic CNV, and NIPT combining with maternal age, maternal serum screening or fetal ultrasound scanning, which improved the screening performance. CONCLUSION: The combined application of cytogenetic karyotyping and CNV-Seq significantly improved the detection rate of fetal pathogenic chromosome microdeletion/duplication. NIPT was recommended for the screening of pathogenic chromosome microdeletion/duplication, and NIPT combining with other screening methods further improved the screening performance for pathogenic fetal CNV.

Association of Elevated Maternal Serum Total Bile Acids With Low Birth Weight and Intrauterine Fetal Growth Restriction.

Importance: Bile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear. Objective: To investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR. Design, Setting, and Participants: This retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020. Exposures: Maternal sTBA concentration during pregnancy. Main Outcomes and Measures: Fetal birth weight and probability of low birth weight (LBW) and IUGR. Results: This study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 µg/mL, 3290 [3.9] g; and for 4.1 µg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 µg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 µg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 µg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28). Conclusions and Relevance: This study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.

Performance of a targeted cell-free DNA prenatal test for 22q11.2 deletion in a large clinical cohort.

OBJECTIVE: 22q11.2 deletion is more common than trisomies 18 and 13 combined, yet no routine approach to prenatal screening for this microdeletion has been established. This study evaluated the clinical sensitivity and specificity of a targeted cell-free DNA (cfDNA) test to screen for fetal 22q11.2 deletion in a large cohort, using blinded analysis of prospectively enrolled pregnancies and stored clinical samples. METHODS: In order to ensure that the analysis included a meaningful number of cases with fetal 22q11.2 deletion, maternal plasma samples were obtained by prospective, multicenter enrolment of pregnancies with a fetal cardiac abnormality and from stored clinical samples from a research sample bank. Fetal genetic status, as evaluated by microarray analysis, karyotyping with fluorescence in-situ hybridization or a comparable test, was available for all cases. Samples were processed as described previously for the Harmony prenatal test, with the addition of DANSR (Digital Analysis of Selected Regions) assays targeting the 3.0-Mb region of 22q11.2 associated with 22q11.2 deletion syndrome. Operators were blinded to fetal genetic status. Sensitivity and specificity of the cfDNA test for 22q11.2 deletion were calculated based on concordance between the cfDNA result and fetal genotype. RESULTS: The final study group consisted of 735 clinical samples, including 358 from prospectively enrolled pregnancies and 377 stored clinical samples. Of 46 maternal plasma samples from pregnancies with a 22q11.2 deletion, ranging in size from 1.25 to 3.25 Mb, 32 had a cfDNA result indicating a high probability of 22q11.2 deletion (sensitivity, 69.6% (95% CI, 55.2-80.9%)). All 689 maternal plasma samples without a 22q11.2 deletion were classified correctly by the cfDNA test as having no evidence of a 22q11.2 deletion (specificity, 100% (95% CI, 99.5-100%)). CONCLUSIONS: The results of this large-scale prospective clinical evaluation of the sensitivity and specificity of a targeted cfDNA test for fetal 22q11.2 deletion demonstrate that this test can detect the common and smaller, nested 22q11.2 deletions with a low (0-0.5%) false-positive rate. Although the positive predictive value (PPV) observed in this study population was 100%, the expected PPV in the general pregnant population is estimated to be 12.2% at 99.5% specificity and 41.1% at 99.9% specificity. The use of this cfDNA test to screen for 22q11.2 deletion could enhance identification of pregnancies at risk for 22q11.2 deletion syndrome without significantly increasing the likelihood of maternal anxiety and unnecessary invasive procedures related to a false-positive result. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Predictability of Macrosomic Birth based on Maternal Factors and Fetal Aneuploidy Screening Biochemical Markers in Hyperglycemic Mothers.

Background: Macrosomic birth weight has been implicated as a significant risk factor for developing various adult metabolic diseases such as diabetes mellitus and coronary heart diseases; it has also been associated with higher incidences of complicated births. This study aimed to examine the predictability of macrosomic births in hyperglycemic pregnant women using maternal clinical characteristics and serum biomarkers of aneuploidy screening performed in the first half of pregnancy. Methods: A retrospective observational study was performed on a cohort of 1,668 pregnant women who 1) had positive outcomes after undergoing 50-g oral glucose challenge test (OGCT) at two university-based hospitals and 2) underwent any one of the following maternal biomarker screening tests for fetal aneuploidy: triple test, quadruple test, and integrated test. Logistic regression-based models for predicting macrosomic births using maternal characteristics and serum biomarkers were developed and evaluated for prediction power. A nomogram, which is a graphical display of the best predictable model, was then generated. Results: The study cohort included 157 macrosomic birth cases defined as birth weight ≥3,820 g, which was equivalent to the top 10 percentile of the modeling cohort. Three primary models solely based on serum biomarkers achieved area under curves (AUCs) of 0.55-0.62. Expanded models, including maternal demographic and clinical factors, demonstrated an improved performance by 25% (AUCs, 0.69-0.73). Conclusion: Our prediction models will help to identify pregnancies with an elevated risk of macrosomic births in hyperglycemic mothers using maternal clinical factors and serum markers from routine antenatal screening tests. Prediction of macrosomic birth at mid-pregnancy may allow customized antenatal care to reduce the risk of macrosomic births.

Can complete blood count parameters that change according to trimester in pregnancy be used to predict severe preeclampsia?

We aimed to evaluate the effectiveness of changes over time in complete blood count (CBC) parameters to estimate the diagnosis of preeclampsia. Data on 161 severe preeclampsia patients and 161 healthy pregnant patients who met the study criteria of pregnant women whose CBC had been measured at 10-12, 22-24 and 28-30 weeks of pregnancy were compared. In the preeclampsia group, an increase in the mean platelet volume (MPV) value and a decrease in the number of platelets were statistically significant in the transition from the second to the third trimester. MPV and lymphocyte counts were more significant in the third trimester and neutrophil lymphocyte ratio (NLR) were more significant in the second trimester. We found that evaluation of the changes in lymphocyte, MPV and NLR values in three different trimesters of pregnancy rather than a single trimester was more meaningful to predict severe preeclampsia.Impact StatementWhat is already known on this subject? Studies have shown that MPV and NLR can predict preeclampsia. However, a clear cut off value could not be determined. The reasons for this may be that the gestational week during which the measurement is made is not standard and the patient groups are not homogeneous.What the results of this study add? In this study, CBC parameters at different stages of the preeclampsia process were compared in the severe preeclampsia group. According to our results, lymphocytes, NLR and MPV can be used to predict severe preeclampsia. In addition, NLR measurements in the second trimester and MPV and lymphocyte measurements in the third trimester were found to be more significant in predicting severe preeclampsia.What the implications are of these findings for clinical practice and/or further research? In order to predict severe preeclampsia, instead of a single measurement of CBC parameters, new calculations should be made that add change over time.

Contribution of blood detection of insulin-like growth factor binding protein-1 for the diagnosis of amniotic-fluid embolism: a retrospective multicentre cohort study.

OBJECTIVE: To assess the contribution of maternal blood detection of IGFBP-1 for the diagnosis of amniotic-fluid embolism in clinical daily practice. DESIGN: A retrospective multicentre cohort study. SETTING: Three tertiary care obstetric units in France. SAMPLE: Data of 86 women for whom amniotic-fluid embolism had been suspected and maternal serum detection of IGFBP-1 had been performed between 2011 and 2019 were analysed. METHODS: The criteria defined by the United Kingdom Obstetric Surveillance System (UKOSS) were used for the retrospective diagnosis of amniotic-fluid embolism. The more structured definition proposed by the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation (SMFM) was also used as secondary endpoint. MAIN OUTCOME MEASURES: Agreements between biological and clinical assessments were tested. The performance of blood detection of IGFBP-1 for the diagnosis of amniotic-fluid embolism according to the UKOSS criteria, and to the SMFM definition, was also assessed. RESULTS: There was only slight agreement between clinical and laboratory diagnosis of amniotic-fluid embolism (Cohen's Kappa coefficient: 0.04). Blood detection of IGFBP-1 had a sensitivity of 16%, a specificity of 88%, a positive and a negative likelihood ratio of 1.3 and 0.95, respectively, and a positive and a negative predictive value of 58 and 50%, respectively, for the diagnosis of amniotic-fluid embolism based on the UKOSS criteria. The use of the more structured SMFM definition of amniotic-fluid embolism did not substantially change the results. CONCLUSION: These results question the usefulness of blood detection of IGFBP-1 for the early diagnosis of amniotic-fluid embolism in daily clinical practice. TWEETABLE ABSTRACT: This retrospective multicentre study questions the contribution of IGFBP-1 detection for the diagnosis of AFE.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

OBJECTIVE: To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. RESULTS: The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. CONCLUSION: Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal thyroid profile in first and second trimester of pregnancy is correlated with gestational diabetes mellitus through machine learning.

There is evidence about a possible relationship between thyroid abnormalities and gestational diabetes mellitus (GDM). However, there is still no conclusive data on this dependence, since no strong correlation has been proved. In this work, we used machine learning to determine whether there is a correlation between maternal thyroid profile in first and second trimester of pregnancy and GDM. Using principal component analysis, it was possible to find an evident correlation between both, which could be used as a complement for a more sensitive GDM diagnosis.

Investigation of copeptin levels in foetal congenital central nervous system anomalies.

Copeptin has been shown to be associated with central nervous system pathologies. The aim of this study was to investigate the relationship between serum CCP levels and central nervous system (CNS) anomalies. In this case-control study, those at 9-14 weeks of gestation serum levels of copeptin, were assessed in pregnant women whose foetuses subsequently developed CNS anomalies (group 1: n = 60) and compared with gestational age-matched pregnant women who exhibited normal pregnancy outcomes (group 2: n = 48). The mean copeptin levels were 1.58 ± 0.40 ng/mL and 1.11 ± 0.36 ng/mL in the CNS anomalies and control groups, respectively (p < .0001). An increased level of copeptin independently predicts development of CNS anomalies, suggesting that copeptin can be used for prediction and discrimination of CNS anomalies in normal pregnancies at 9-14 weeks of gestation.Impact statementWhat is already known on this subject? There is no test or method to diagnose CNS anomalies in the first trimester of pregnancy. This study presents the first and new information on the relationship between serum copeptin levels and central nervous system anomalies in pregnant women whose foetuses subsequently developed CNS anomalies.What do the results of this study add? I have strongly demonstrated differences in maternal CPP levels between CNS anomalous pregnancies and healthy controls.What are the implications of these findings for clinical practice and/or further research? It has been thought that copeptin appears to be an ideal marker for central nervous system anomaly prediction at 9-14 weeks of gestational age and if confirmed in larger prospective studies. Finally, these results could not be used as parameters for prenatal CNS screening. Advanced studies, well-structured and conducted on larger populations are needed to investigate the issue further.

Relations between second-trimester aneuploidy screening results and prediction of labour induction success in term pregnancies.

We aimed to assess whether the second-trimester maternal serum markers could be used for the prediction of labour induction success. This prospective study enrolled women planned labour induction at term. Women were assigned to one of two groups: vaginal prostaglandin or balloon dilatation. All patients were evaluated for Bishop score, maternal serum oestriol, human chorionic gonadotropin and progesterone at the time of second-aneuploidy screening. The total successful rate for induction of labour was 63.9% in both groups. Maternal serum oestriol multiple of median (MoM) values were significantly lower among the caesarean section group compared to the vaginal delivery group (p < .001). A MoM value of 0.74 for oestriol was associated with a sensitivity of 75.9%, specificity of 41.0%, a positive predictive value of 76.6% and a negative predictive value of 58.0% for a successful induction of labour. Oestriol had a good performance in the prediction of successful induction of labour at term.IMPACT STATEMENTWhat is already known on this subject? Induction of labour is a common procedure undertaken whenever the benefits of prompt delivery outweigh the risks of expectant management. Previous studies have reported that a decreased progesterone/oestradiol ratio and increased maternal plasma oestriol levels are associated with successful labour. What the results of this study add? The results of this study showed that second-trimester oestriol multiple of median (MoM) value provide a significant contribution to the efforts of the prediction of successful induction of labour in term pregnancy, having a sensitivity of 69.8%, specificity of 92.4%, positive predictive value of 83.3% and negative predictive value of 82.5%.What the implications are of these findings for clinical practice and/or further research? This finding can be used as an additional method for prediction of labour induction as well as multiparity and Bishop score. This adds new valuable data to the literature which could be used for systematic reviews and for implementing guidelines and protocols on labour induction.

Impact of mosaicism ratio on positive predictive value of cfDNA screening.

OBJECTIVE: To examine the relationship between the fraction of cell-free DNA (cfDNA) affected by aneuploidy compared to the overall fetal fraction of a prenatal screening specimen and its effect on positive predictive value (PPV). METHOD: CfDNA specimens positive for trisomy 13, 18, and 21 with diagnostic outcomes were analysed over a 22-month period in one clinical laboratory. For each positive specimen, a "mosaicism ratio" (MR) was calculated by dividing the fraction of cfDNA affected by aneuploidy by the overall fetal fraction of the specimen. PPVs were calculated and analyzed based on various MR ranges. RESULTS: Trisomy 13 was the aneuploidy most commonly seen in mosaic form, followed by trisomy 18 and trisomy 21. Significant differences in positive predictive values were noted for all three trisomies between samples with an MR in the "mosaic" versus "non-mosaic" range, as well as between results classified as "low-mosaic" versus "high-mosaic." CONCLUSION: PPVs may be influenced, in part, by the mosaicism ratio associated with a particular result. The data generated from this study may be useful in providing more personalized risk assessments for patients with positive cfDNA screening results.

Association of adverse outcomes of intrahepatic cholestasis of pregnancy with zonulin levels.

Our aim was to investigate serum zonulin levels in intrahepatic cholestasis of pregnancy (ICP) and to determine the usefulness of zonulin in ICP follow-up. A prospective case-control study was carried out which included 88 pregnant women (44 patients with ICP and 44 controls). Maternal serum samples obtained from all participants and zonulin levels were determined by enzyme-linked immunosorbent assay (ELISA). Compared with controls, women with ICP had significantly higher zonulin levels (mean 0.728 ± 0.520 ng/mL vs. 1.303 ± 0.63 ng/mL, p <.001). According to the receiver operating characteristic (ROC) analysis performed for the predictive value of zonulin levels for ICP, the area under the curve (AUC) was 0.761 (95% CI: 0.661-0.860). Multivariable logistic regression analysis revealed serum zonulin levels was independently associated with adverse perinatal outcomes (OR = 1.278, 95% CI: 0.232-7.041), severity ICP (OR: 7.535, 95% CI: 1.597-13.553) and also unresponsiveness to treatment in ICP (OR: 4.178, 95% CI: 0.929-8.784).IMPACT STATEMENTWhat is already known on this subject? Zonulin is a regulator protein that increases the intestinal permeability by modulating the intercellular tight junctions (TJ). It is the only physiological protein known to control intestinal permeability and damage of the intestinal barrier is one of the causes of absorption disorders, inflammation and autoimmunity. ICP is a relatively non-threatening condition to women but is linked with a higher risk of preterm delivery, foetal distress and foetal death.What do the results of this study add? This study showed that increased levels of zonulin are associated with adverse perinatal outcomes, severity of ICP and unresponsiveness to treatment in ICP.What are the implications of these findings for clinical practice and/or further research? Focussing on preservation of intestinal permeability may be an alternative preventive strategy to reduce the adverse perinatal outcomes and severity of ICP. Further longitudinal studies are needed to verify the relationships among zonulin levels and pregnancy-related diseases.

Maternal serum endothelial cell-specific molecule-1 level and its correlation with severity of early-onset preeclampsia.

Preeclampsia (PE), the primary pathology of which is endothelial cell (EC) dysfunction, has long-lasting effects such as cardiovascular disease. Therefore, it was decided to investigate the maternal serum concentrations of EC-specific molecule-1 in patients with early-onset preeclampsia (E-PE). This study was conducted on 33 pregnant women with E-PE and 35 healthy pregnant women matched for gestational age. EC-specific molecule-1 level was measured using a commercially available enzyme-linked immunosorbent assay kit. The mean EC-specific molecule-1 concentrations were not significantly different between the groups (651.7 ± 632.2 pg/mL vs. 425.9 ± 263.0 pg/mL, p=.056). Among women with E-PE, the median EC-specific molecule-1 concentration did not differ significantly by disease severity (p=.115). EC-specific molecule-1 is not involved in the pathogenesis of E-PE. However, some studies in the literature report that EC-specific molecule-1 concentrations increased during the diagnosis of PE. Therefore, well-designed studies with a large sample are needed in cases of E-PE.Impact StatementWhat is already known on this subject? There is an increased risk of cardiovascular disease (CVD) in early-onset preeclampsia (E-PE) which is linked with endothelial dysfunction. Endothelial cell (EC)-specific molecule-1 stands out as an important marker in EC dysfunction related conditions such as preeclampsia.What the results of this study add? This study showed that EC-specific molecule-1 is not associated with the CVDs risk linked with endothelial dysfunction in E-PE. Additionally, there was also no significant relationship was detected between the severity of E-PE and EC-specific molecule-1 concentrations.What the implications are of these findings for clinical practice and/or further research? Endothelial cell-specific molecule-1 is not involved in the pathogenesis of E-PE. Moreover, advantageous and easy-to-measure markers are needed in larger sample studies to better understand the aetiology of E-PE.

Expression levels of maternal plasma microRNAs in preeclamptic pregnancies.

The present study aimed to identify the differential expression profiles of microRNAs in the plasma between patients with preeclampsia (PE) and healthy pregnancies using quantitative real-time PCR. The expression profiles of 32 miRNAs in maternal plasma from 31 patients with PE and 32 healthy pregnancies were evaluated. The expression levels of eight miRNAs including miR-210, miR-375, miR-197-3p, miR-132-3p, miR-29a-3p, miR-328, miR-24-3p, and miR-218-5p were significantly upregulated and the expression levels of three miRNAs, including miR-302b-3p, miR-191-5p, and miR-17-5p, were significantly downregulated in patients with preeclampsia when compared to healthy pregnant women. In conclusion, we identified 11 miRNAs that may be potential biomarkers for non-invasive diagnosis and a pivotal role in the prediction of PE. Considering the small cohort of patients, further studies with larger samples from different gestational stages are necessary to confirm our findings.IMPACT STATEMENTWhat is already known on this subject? The alterations in the release pattern of placenta-specific miRNAs detected in maternal serum have been found to be associated with pregnancy-related complications such as preeclampsia (PE).What do the results of this study add? In the present study, the release pattern of seven miRNAs had consistency and two of them had inconsistency with previous researches. Moreover, two novel miRNAs were also defined to demonstrate the interrelationship between PE and miRNAs.What are the implications of these findings for clinical practice and/or future research? The identification of 11 miRNAs that may be potential biomarkers for non-invasive diagnosis and a pivotal role in the prediction of PE. Considering the small cohort of patients, further studies with larger samples from different gestational stages are necessary to confirm our findings.

Effect of anti-epileptic drugs on first trimester screening test results.

OBJECTIVE: To evaluate first trimester screening test parameters in epileptic patients using anti-epileptic drugs. MATERIALS AND METHODS: We retrospectively evaluated first trimester screening test results of 23 epileptic pregnant women using anti-epileptic drugs with a control group consisting of 92 healthy pregnancies. The anti-epileptic drugs used in this study were carbamazepine, levatiracetam, valproic acid and lamotrigine. Single drug or multi-drug regimens were used according to the clinical conditions. Patients with any known chronic or acute disease and drug usage were excluded from the study. Comparisons were performed via Mann-Whitney U test. RESULTS: First trimester screening test biochemical markers were compared and maternal serum PAPP-A MoM values were found to be similar in study and control groups while ß-hCG MoM values were significantly higher in pregnancies using epileptic drugs (p: 0,737 and p < 0.001, respectively). CONCLUSION: Biochemical first trimester screening test results may be affected by anti-epileptic drug usage, which may lead to misinterpretation of the risk level. Thus, validation of MoM values should be necessary in order to obtain optimal results.

Frequency and clinical manifestation of prenatal cytogenetic diagnosis of chromosomal polymorphisms in Northeast China.

OBJECTIVE: To retrospectively analyze the incidence of chromosomal polymorphisms in prenatal cytogenetic diagnostic cases and the effect of the clinical manifestation of these fetuses. MATERIALS AND METHODS: 490 fetuses with chromosomal polymorphisms among 9996 pregnant women who underwent prenatal cytogenetic diagnosis were included in this study and were set as group 1. Other 500 pregnant women, whose fetuses were with normal karyotypes, were randomly selected from the remaining pregnant women and set as group 2. Clinical information and outcomes and maternal serum screening results of group 1 were compared with group 2. RESULTS: The frequency of fetal chromosomal polymorphism was 4.90% (490/9996). The most common variants observed were 1/9/16 qh± (2.27%, 227/9996), followed by inv(9) (0.90%, 90/9996). 94.62% (264/279) of fetal chromosomal variants were inherited from parents. No statistical difference was found in clinical information and outcomes and maternal serum screening results between group 1 and group 2. CONCLUSION: The fetus with chromosomal polymorphism has no impact on serum markers of second trimester screening and does not play an important role for the clinical outcome of the current pregnancy either, whether it is inherited from the parents or a de novo mutation.

Competing-risks model for prediction of small-for-gestational-age neonate from maternal characteristics and serum pregnancy-associated plasma protein-A at 11-13 weeks' gestation.

OBJECTIVES: To develop a continuous likelihood model for pregnancy-associated plasma protein-A (PAPP-A), in the context of a new competing-risks model for prediction of a small-for-gestational-age (SGA) neonate, and to compare the predictive performance of the new model for SGA to that of previous methods. METHODS: This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. The dataset was divided randomly into a training dataset and a test dataset. The training dataset was used for PAPP-A likelihood model development. We used Bayes' theorem to combine the previously developed prior model for the joint Gaussian distribution of gestational age (GA) at delivery and birth-weight Z-score with the PAPP-A likelihood to obtain a posterior distribution. This patient-specific posterior joint Gaussian distribution of GA at delivery and birth-weight Z-score allows risk calculation for SGA defined in terms of different birth-weight percentiles and GA. The new model was validated internally in the test dataset and we compared its predictive performance to that of the risk-scoring system of the UK National Institute for Health and Care Excellence (NICE) and that of logistic regression models for different SGA definitions. RESULTS: PAPP-A has a continuous association with both birth-weight Z-score and GA at delivery according to a folded-plane regression. The new model, with the addition of PAPP-A, was equal or superior to several logistic regression models. The new model performed well in terms of risk calibration and consistency across different GAs and birth-weight percentiles. In the test dataset, at a false-positive rate of about 30% using the criteria defined by NICE, the new model predicted 62.7%, 66.5%, 68.1% and 75.3% of cases of a SGA neonate with birth weight < 10th percentile delivered at < 42, < 37, < 34 and < 30 weeks' gestation, respectively, which were significantly higher than the respective values of 46.7%, 55.0%, 55.9% and 52.8% achieved by application of the NICE guidelines. CONCLUSIONS: Using Bayes' theorem to combine PAPP-A measurement data with maternal characteristics improves the prediction of SGA and performs better than logistic regression or NICE guidelines, in the context of a new competing-risks model for the joint distribution of birth-weight Z-score and GA at delivery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Cell-free DNA screening in twin pregnancies: A more accurate and reliable screening tool.

OBJECTIVE: Outcome data from cell-free DNA (cfDNA) screening in twin gestations are limited. This study adds an appreciable number of confirmed outcomes to the literature, and assesses performance of cfDNA screening in twins over a 4.5-year period at one large clinical laboratory. METHOD: Prenatal cytogenetic and SNP microarray results were cross-referenced with cfDNA results for twin pregnancies, yielding 422 matched cases. Using diagnostic results as truth, performance of cfDNA screening in this population was assessed. RESULTS: Of the 422 twin pregnancies with both cfDNA and diagnostic results, 3 specimens failed amniocyte analysis, and 48 samples (11.5%) were nonreportable from the initial cfDNA draw. Analysis of the 371 reportable samples demonstrated a collective sensitivity of 98.7% and specificity of 93.2% for trisomies 21/18/13. Positive predictive values (PPVs) in this study population, which is enriched for aneuploidy, were 78.7%, 84.6%, and 66.7% for trisomy 21, 18, and 13, respectively. CONCLUSION: CfDNA screening in a cohort of twin pregnancies with matched diagnostic results showed superior performance compared to traditional serum biochemical screening in twins. This study adds to a growing body of evidence suggesting that cfDNA is an accurate and reliable screening tool for the major trisomies in twin pregnancies.