Discovery and Verification of Extracellular miRNA Biomarkers for Non-invasive Prediction of Pre-eclampsia in Asymptomatic Women.

Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later developed pre-eclampsia. Sera collected from 73 pre-eclampsia cases and 139 controls between 17 and 28 weeks gestational age (GA), divided into separate discovery and verification cohorts, are analyzed by small RNA-seq. Discovery and verification of univariate and bivariate miRNA biomarkers reveal that bivariate biomarkers verify at a markedly higher rate than univariate biomarkers. The majority of verified biomarkers contain miR-155-5p, which has been reported to mediate the pre-eclampsia-associated repression of endothelial nitric oxide synthase (eNOS) by tumor necrosis factor alpha (TNF-α). Deconvolution analysis reveals that several verified miRNA biomarkers come from the placenta and are likely carried by placenta-specific extracellular vesicles.

The Number of Circulating Fetal Extravillous Trophoblasts Varies from Gestational Week 6 to 20.

Cell-based non-invasive prenatal testing (cbNIPT) based on circulating fetal extravillous trophoblasts (fEVTs) has shown to be possible in gestational week (GW) 10-13. Prenatal testing is relevant for a wider time period than GW 10-13, but it is unclear if fEVTs are present in sufficient numbers for cbNIPT at other time points during pregnancy. We present the first longitudinal study where the number of circulating fEVTs was determined from the mid first trimester to the mid second, specifically GW 6-8, 12-13, and 19-20. Blood samples from 13 women opting for assisted reproduction were collected at GW 6-8, 12-13, and 19-20. fEVTs were enriched using a magnetic-activated cell sorting system, stained with anti-cytokeratin antibodies, and fEVTs were identified with the use of a MetaSystem fluorescence microscope scanner. Blood samples drawn at GW 6-8 yielded an average of 5.5 fEVTs per 30 mL of blood. This increased significantly to an average of 11.8 in GW 12-13 (P value: 0.0070, Mann-Whitney test), and decreased significantly to an average of 5.3 in GW 19-20 (P value: 0.0063, Mann-Whitney test). In 9 out of 13 cases, the number of fEVTs peaked in GW 12-13 compared to GW 6-8 and GW 19-20. For the majority of cases, fEVTs can be identified at GW 6-8 and GW 19-20, but the highest number of fEVTs is observed at GW 12-13 indicating this is the optimal time point for cbNIPT.

Reaching hard-to-reach men through home-based couple HIV testing among pregnant women and their male partners in western Kenya: a qualitative study.

BACKGROUND: Globally only 79% of adults living with HIV (human immunodeficiency virus) know their status and men in sub-Saharan Africa are considered a particularly hard-to-reach population for HIV testing. Home-based HIV couple testing during the antenatal period is a safe and effective method that has been used to test male partners of pregnant women. The goal of this qualitative study was to identify elements that made couple testing successful and describe important characteristics of this home-based intervention from couples' perspectives. METHODS: Couples who received scheduled home-based couple testing during pregnancy in Kisumu, Kenya, were purposively sampled based on HIV status from January to May 2015. An interviewer administered all of the in-depth interviews and two coders were directly involved in the data analysis and reconciled codes several times in the process. RESULTS: Twenty-one couples were enrolled: 9 concordant HIV-negative couples, 8 HIV discordant couples, 3 HIV concordant HIV-positive couples, and 1 whose concordance status was unknown. Median age at the time of home-based couple testing was 24 and 28 years for women and men, respectively. Median relationship duration was 3 years and couples had a median of two pregnancies. The major themes that emerged were that home-based couple testing 1) removed the female burden of requesting couple testing, 2) overcame logistical barriers associated with clinic-based testing, 3) encouraged participants to overcome their fear of testing and disclosure, 4) provided privacy in the home, and 5) provided quality time with the health advisors. Importantly, some women appreciated individual testing at the clinic before couple testing and some couples preferred skilled, anonymous health advisors delivering the intervention rather than known community health workers. CONCLUSIONS: The results of this qualitative study suggest that home-based couple testing during pregnancy overcame many of the barriers that limit men's access to and uptake of clinic-based testing. It encouraged participants to overcome their fear of testing and disclosure through a setting that afforded privacy and quality time with skilled health advisors. These qualitative results may help design effective partner and couple HIV testing programs in the antenatal setting and alongside or within other assisted partner notification services. TRIAL REGISTRATION: Clinicaltrials.gov registry: NCT01784783. Registered prospectively on June 15, 2012.

Ultrasound features prior to 11 weeks' gestation and first-trimester maternal factors in prediction of hypertensive disorders of pregnancy.

OBJECTIVES: Maternal hypertensive disorders (MHD), including pregnancy-induced hypertension and pre-eclampsia, are estimated to occur in 7-10% of pregnancies worldwide and have significant short- and long-term implications for both mother and fetus. This study aimed to determine the association of conventional and novel early first-trimester ultrasound measures with MHD and whether these ultrasound measures, combined with maternal characteristics and biochemistry, improve the prediction of MHD. METHODS: This was a prospective cohort study of consecutive women with a singleton pregnancy, attending for an early (5 + 1 to 11 + 0 weeks' gestation) ultrasound examination at a private obstetric ultrasound practice between February 2016 and August 2018. Recorded ultrasound measurements included mean sac diameter, yolk sac diameter, crown-rump length, fetal heart rate (FHR), trophoblast thickness, trophoblast volume (TV) and mean uterine artery pulsatility index. Maternal biochemistry was assessed at 10-14 weeks and included beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and maternal serum alpha-fetoprotein. Regression models were fitted for each ultrasound parameter and multiples of the median (MoM) were calculated. All measures were compared between women who had a normotensive outcome and those who subsequently developed MHD. Logistic regression analysis was used to create a prediction model for MHD based on maternal characteristics, ultrasound measurements at 5 + 1 to 11 + 0 weeks' gestation and maternal biochemistry at 10-14 weeks. RESULTS: In total, 1141 women were included in the analysis, of whom 1086 (95.2%) were normotensive at delivery and 55 (4.8%) developed MHD. Women who developed MHD weighed significantly more than did normotensive women (P < 0.0001). Mean MoM values for TV (P = 0.006), PAPP-A (P = 0.031) and PlGF (P = 0.044) were decreased significantly in pregnancies that subsequently developed MHD. The proposed logistic regression model includes maternal weight and height and MoM values for TV, FHR and PlGF, resulting in an area under the receiver-operating-characteristics curve of 0.80 (95% CI, 0.75-0.86). CONCLUSION: The combination of maternal weight and height, TV and FHR, measured prior to 11 weeks' gestation, and first-trimester PlGF appears to have good predictive value for development of MHD later in pregnancy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Copeptin and mid-regional pro-atrial natriuretic peptide in women with suspected or confirmed pre-eclampsia: comparison with sFlt-1/PlGF ratio.

OBJECTIVES: Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) may contribute to the pathogenesis of pre-eclampsia (PE), but their role remains to be elucidated. Our aims were to evaluate the surrogates of AVP and ANP, C-terminal pro-AVP (copeptin) and mid-regional pro-ANP (MR-proANP), as biomarkers for the prediction of PE-related pregnancy complications and whether they are associated with angiogenic markers and/or clinical manifestations of PE. METHODS: This was a retrospective analysis of a prospective cohort study that enrolled pregnant women with suspected or confirmed PE, between December 2013 and April 2016. From each patient, a blood sample was obtained at study entry and serum levels of copeptin, MR-proANP, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. We evaluated the ability of sFlt-1, PlGF, sFlt-1/PlGF ratio, copeptin and MR-proANP, assessed either alone or combined with traditional predictors (gestational age, parity, diastolic blood pressure and proteinuria), to predict maternal complications and fetal/neonatal complications. Models were compared using concordance statistic (C-index). RESULTS: A total of 526 women were evaluated in the study. Women with confirmed PE displayed elevated serum copeptin and MR-proANP levels in comparison to those with suspected PE but no hypertensive disease of pregnancy. When combined with traditional predictors, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP (0.76, 0.63 and 0.67, respectively, vs 0.60 for the traditional predictors alone) for the prediction of maternal complications. Similarly, for the prediction of fetal/neonatal complications, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP when added to the traditional model (0.83, 0.79 and 0.80, respectively, vs 0.79 for the traditional predictors alone). When subdividing women according to sFlt-1/PlGF ratio (≥ 85 vs < 85), no differences in copeptin levels were observed, while MR-proANP level was elevated in women with sFlt-1/PlGF ratio ≥ 85. Multiple regression analysis revealed that copeptin and MR-proANP were independent determinants of proteinuria. CONCLUSIONS: Copeptin and MR-proANP have limited value in predicting PE-related complications when compared with the sFlt-1/PlGF ratio. However, both copeptin and MR-proANP were associated with proteinuria, with copeptin exerting this effect independently of the sFlt-1/PlGF ratio. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Cell-free DNA for Down syndrome screening in obese women: Is it a cost-effective strategy?

OBJECTIVE: Determine cost differences between cell-free DNA (cfDNA) and serum integrated screening (INT) in obese women given the limitations of aneuploidy screening in this population. METHODS: Using a decision-analytic model, we estimated the cost-effectiveness of trisomy 21 screening in class III obese women using cfDNA compared with INT. Primary outcomes of the model were cost, number of unnecessary invasive tests, procedure-related fetal losses, and missed cases of trisomy 21. RESULTS: In base case, the mean cost of cfDNA was $498 greater than INT ($1399 vs $901). cfDNA resulted in lower probabilities of unnecessary invasive testing (2.9% vs 3.5%), procedure-related loss (0.015% vs 0.019%), and missed cases of T21 (0.00013% vs 0.02%). cfDNA cost $87 485 per unnecessary invasive test avoided, $11 million per procedure-related fetal loss avoided, and $2.2 million per missed case of T21 avoided. In sensitivity analysis, when the probability of insufficient fetal fraction is assumed to be >25%, cfDNA is both costlier than INT and results in more unnecessary invasive testing (a dominated strategy). CONCLUSION: When the probability of insufficient fetal fraction more than 25% (a maternal weight of ≥300 lbs), cfDNA is costlier and results in more unnecessary invasive testing than INT.

BACs-on-Beads™ assay, a rapid aneuploidy test, improves the diagnostic yield of conventional karyotyping.

BACs-on-Beads (BoBs™) assay is a rapid aneuploidy test (RAT) that detects numerical chromosomal aneuploidies and multiple microdeletion/microduplication syndromes. This study was conducted to appraise the usefulness of the BoB™ assay as a complementary diagnostic tool to conventional karyotyping for the rapid detection of chromosomal aneuploidies. A total of 485 prenatal (amniotic fluid and chorionic villi) and blood/products of conception samples were collected between July 2013 and August 2018, and analyzed by the BoBs™ assay and cytogenetic karyotyping and further validated by fluorescence in situ hybridization (FISH). Forty-three of 484 qualifying samples (8.9%) were identified as abnormal by the BoBs™ assay. The assay was comparable to karyotyping in the detection of common structural abnormalities (trisomy 21, trisomy 18, X, and Y), with a sensitivity of 96.0% and a specificity of 100%. BoBs™ assay detected 20 microdeletion and microduplication syndromes that were missed by karyotyping. BoBs™, however, missed 10 cases of polyploidies and chromosomal rearrangements which were identified by conventional karyotyping. Our findings suggest that BoBs™ is a reliable RAT which is suitable in combination with conventional karyotyping for the detection of common aneuploidies. The assay also improves the diagnostic yield by recognizing clinically relevant submicroscopic copy number gains and losses.

First trimester combined screening biochemistry in detection of congenital heart defects.

Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fß-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs). Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down's syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland. Results: Both PAPP-A and fß-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fß-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fß-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively. Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fß-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans.

Evaluation of agreement of placental growth factor (PlGF) tests and the soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio, comparison of predictive accuracy for pre-eclampsia, and relation to uterine artery Doppler and response to aspirin.

OBJECTIVES: The objective of this study is to evaluate agreement between PlGF and sFlt-1/PlGF ratio tests and compare their predictive accuracy for pre-eclampsia in high-risk women. Also, to examine for associations of abnormal PlGF or sFlt-1/PlGF ratio with abnormal uterine artery Doppler and platelet response to aspirin. METHODS: Prospective cohort study, 150 pregnant women at high risk of pre-eclampsia prescribed 75 mg aspirin daily. Uterine artery Dopplers were assessed at 20+0-23+6 weeks. At 33+0-35+6 weeks platelet function aspirin metabolites, PlGF and the sFlt-1/PlGF ratio were measured. OUTCOME: Measures were all pre-eclampsia and pre-eclampsia requiring delivery prior to 37 weeks. RESULTS: Overall percent agreement was 89.3% for PlGF tests but 74.7-78% for PlGF tests and the sFlt-1/PlGF ratio. AUCs were 0.70-0.75 for prediction of any pre-eclampsia and 0.92-0.99 for preterm pre-eclampsia. We found a significant association between abnormal PlGF or sFlt-1/PlGF ratio and abnormal uterine artery Doppler (χ2 5.47, p = .019), but no association with platelet response to aspirin (χ2 0.12, p = .913). There were no associations between suboptimal aspirin adherence and either abnormal angiogenic markers or uterine artery Dopplers (χ2 0.144, 0.038, p = .704, .846, respectively). CONCLUSIONS: There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin.

Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study.

OBJECTIVE: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women. METHODS: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay. RESULTS: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks. CONCLUSION: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction.

Reference Ranges and Determinants of Thyroid Function During Early Pregnancy: The SELMA Study.

Context: Establishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for triiodothyronine measurements, and most studies do not take into account thyroid antibodies or human chorionic gonadotropin. Objective: To determine reference ranges and to identify/quantify determinants of TSH, free T4 (FT4), free triiodothyronine (FT3), total T4 (TT4), and total triiodothyronine (TT3). Design, Setting, and Participants: This study included 2314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5th to 97.5th percentiles after excluding thyroperoxidase antibody (TPOAb)-positive and/or thyroglobulin antibody (TgAb)-positive women. Intervention: None. Main Outcome Measures: TSH, FT4, FT3, TT4, and TT3 in prenatal serum. Results: After exclusion of TPOAb-positive women, reference ranges were as follows: TSH, 0.11 to 3.48 mU/L; FT4, 11.6 to 19.4 pmol/L; FT3, 3.72 to 5.92 pg/mL; TT4, 82.4 to 166.2 pmol/L; and TT3, 1.28 to 2.92 nmol/L. Additional exclusion of TgAb-positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. Body mass index (BMI) and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4, and TT3. Conclusions: We show that the exclusion of TgAb-positive women on top of excluding TPOAb-positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4, and TT3 that could reflect endocrine-disrupting effects and/or effects on thyroid hormone transport or deiodination.

Noninvasive Prenatal Testing of Rare Autosomal Aneuploidies by Semiconductor Sequencing.

Rare autosomal aneuploidies (RAAs) can cause miscarriage or other pregnancy complications and lead to inconsistent results of noninvasive prenatal testing (NIPT), but many NIPT providers have not yet started to provide related services. Our aim was to develop a semiconductor sequencing platform (SSP)-based method for detecting RAAs when pregnant women performed NIPT. Fifty-three aneuploidy samples with verified karyotyping or array comparative genomic hybridization (aCGH) results were collected and subjected to RAAs detection using an SSP to develop a method by genomic sequencing. Various trisomies on all chromosomes other than chromosomes 17 and 19, four multiple aneusomies, one monosomy and five sex chromosome abnormalities were got by our method which can directly identify RAAs via a z-score. Then, artificial mixtures of 10% and 5% DNA were created by adding fragmented fifty-three tissue samples and used in an NIPT simulation to develop a bioinformatics analysis method which can use in NIPT. And the results were in accordance with those of karyotyping and aCGH. Therefore, our method has potential for use in NIPT. Finally, 23,823 clinical plasma samples were tested to verify the performance of our approach. Karyotyping or aCGH was performed on the positive clinical samples. In total, 188 of 23,823 clinical samples were positive (T2, n = 1; T7, n = 1; T13, n = 15; T18, n = 45; T21, n = 125; and multiple aneusomies, n = 1) and verified by karyotyping or aCGH; no sample was a false negative. Several false positives were detected, one of which showed maternal copy number variation (CNV). One case of multiple aneusomies was caused by a maternal tumor. The method developed enables detection of RAAs without increasing costs.

Implications of failure to achieve a result from prenatal maternal serum cell-free DNA testing: a historical cohort study.

OBJECTIVE: To investigate the pregnancy outcomes in a cohort of women who failed to obtain a result in non-invasive prenatal testing (NIPT). DESIGN: Historical cohort study. SETTING: A multicentre private practice in Sydney, Australia. POPULATION: Women who failed to obtain a result from NIPT (n = 131). METHODS: The maternal characteristics, antenatal investigations and pregnancy outcomes for these women were compared with those who obtained a result at the same practice and to the general Australian obstetric population. MAIN OUTCOME MEASURES: Antenatal investigations: pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotrophin (ß-hCG), placental growth factor (PlGF), uterine artery pulsatility index (PI), mean arterial pressure (MAP). Pregnancy outcomes: chromosomal abnormality, pre-eclampsia, gestational diabetes, small-for-gestational-age (SGA), preterm delivery. RESULTS: Only 1.1% of NIPT samples failed to return a result. This cohort was significantly older and had significantly increased weight compared with the general Australian obstetric population. Pregnancy outcomes were available for 94% of the cohort. There were significantly higher rates of chromosomal aneuploidies (6.5% versus 0.2%, P < 0.0001), pre-eclampsia (11% versus 1.5%, P < 0.0001) and gestational diabetes (23% versus 7.5%, P < 0.0001) compared with the general obstetric population. Rates of preterm delivery and SGA were elevated but did not reach significance. Antenatal investigations demonstrated decreased PAPP-A MoM (0.75 versus 1.14, P < 0.0001), decreased free ß-hCG (0.71 versus 1.01, P < 0.0001) and increased uterine artery PI (1.79 versus 1.65, P = 0.02). CONCLUSION: Women who fail to obtain a result from NIPT are at increased risk of adverse pregnancy outcomes, in particular chromosomal aneuploidy, gestational diabetes and pre-eclampsia. FUNDING: None received. TWEETABLE ABSTRACT: Women who fail to obtain a result from cell-free DNA NIPT are at increased risk of adverse pregnancy outcomes.

Angiogenic factors: potential to change clinical practice in pre-eclampsia?

Pre-eclampsia is a complex disease with significant maternal and fetal morbidity and mortality. Its syndromic nature makes diagnosis and management difficult. The field is rapidly evolving with the definition of pre-eclampsia being challenged by some organisations, with proteinuria no longer being essential in the presence of other features. In the last decade, angiogenic factors, in particular soluble fms-like tyrosine kinase 1 (sFlt-1), have emerged as important molecules in the pathogenesis of pre-eclampsia. Here we review the most recent evidence regarding the potential of these factors as biomarkers and therapeutic targets for pre-eclampsia. TWEETABLE ABSTRACT: A review of angiogenic factors, sFlt-1 and PlGF, in the diagnosis, prediction and management of pre-eclampsia.

The first trimester combined test for aneuploidies - a single center experience.

PURPOSE: We present the results of the systematic application of the first trimester combined test for aneuploidies, in a Romanian center. METHODS: Since October 2009, in Filantropia Hospital in Bucharest, we have systematically been using the FMF (Fetal Medicine Foundation) combined first trimester test to screen for common aneuploidies at 11 to 13 + 6 weeks of gestation. We assessed the crown to rump length (CRL), nuchal translucency, fetal heart rate as well as PAPP-A, and free ß-hCG in maternal serum. We evaluated additional first trimester ultrasound markers in most of the cases. The individual risk for aneuploidies was calculated using the FMF algorithm. RESULTS: Pregnancy outcome is known for 6030 euploid fetuses and 42 aneuploid fetuses from our screening population. The detection rate for trisomy 21 of the combined test was 87.5% for a screen positive rate of 1.96%. All of the trisomy 18 and trisomy 13 cases were detected prenatally. Some of the trisomy 18 cases proved not to be symptomatic in the first trimester. CONCLUSIONS: Our results are similar to those of the main studies on the FMF method of first trimester screening for aneuploidies. Our numbers are small because of limited availability of the very specialized resources involved.

Practice Bulletin No. 187: Neural Tube Defects.

Neural tube defects (NTDs) are congenital structural abnormalities of the central nervous system and vertebral column. Neural tube defects may occur as an isolated malformation, in combination with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure (1). Neural tube defects are the second-most-common major congenital anomaly (2) after cardiac malformations, and their prevalence varies by geographic region, race, and environmental factors (3). Outcomes and disabilities depend on level and extent of lesion; for instance, anencephaly is incompatible with life but most infants with spina bifida will survive after surgical repair (4). Importantly, and in contrast to many other congenital abnormalities, primary prevention of NTDs is possible with folic acid. In addition, prenatal screening and diagnosis are widely available, and fetal surgery has improved outcomes for some newborns. The purpose of this document is to provide information about NTDs and make management recommendations for the pregnancy complicated by a fetal NTD.

Management of suspected primary Toxoplasma gondii infection in pregnant women in Norway: twenty years of experience of amniocentesis in a low-prevalence population.

BACKGROUND: Primary infection with Toxoplasma gondii during pregnancy may pose a threat to the fetus. Women infected prior to conception are unlikely to transmit the parasite to the fetus. If maternal serology indicates a possible primary infection, amniocentesis for toxoplasma PCR analysis is performed and antiparasitic treatment given. However, discriminating between primary and latent infection is challenging and unnecessary amniocenteses may occur. Procedure-related fetal loss after amniocentesis is of concern. The aim of the present study was to determine whether amniocentesis is performed on the correct patients and whether the procedure is safe for this indication. METHODS: Retrospective study analysing data from all singleton pregnancies (n = 346) at Oslo University Hospital undergoing amniocentesis due to suspected maternal primary toxoplasma infection during 1993-2013. Maternal, neonatal and infant data were obtained from clinical hospital records, laboratory records and pregnancy charts. All serum samples were analysed at the Norwegian Institute of Public Health or at the Toxoplasma Reference Laboratory at Oslo University Hospital. The amniocenteses were performed at Oslo University Hospital by experienced personnel. Time of maternal infection was evaluated retrospectively based on serology results. RESULTS: 50% (173) of the women were infected before pregnancy, 23% (80) possibly in pregnancy and 27% (93) were certainly infected during pregnancy. Forty-nine (14%) women seroconverted, 42 (12%) had IgG antibody increase and 255 (74%) women had IgM positivity and low IgG avidity/high dye test titre. Fifteen offspring were infected with toxoplasma, one of them with negative PCR in the amniotic fluid. Median gestational age at amniocentesis was 16.7 gestational weeks (GWs) (Q1 = 15, Q3 = 22), with median sample volume 4 ml (Q1 = 3, Q3 = 7). Two miscarriages occurred 4 weeks after the procedure, both performed in GW 13. One of these had severe fetal toxoplasma infection. CONCLUSIONS: Half of our study population were infected before pregnancy. In order to reduce the unnecessary amniocenteses we advise confirmatory serology 3 weeks after a suspect result and suggest that the serology is interpreted by dedicated multidisciplinary staff. Amniocentesis is safe and useful as a diagnostic procedure in diagnosing congenital toxoplasma infection when performed after 15 GW.

The usefulness of CYFRA 21-1 to diagnose and predict preeclampsia: a nested case-control study.

BACKGROUND: The ability to identify patients at risk for developing preeclampsia is important for preventing morbidity and mortality in both the mother and child. Although CYFRA 21-1 (a fragment of Cytokeratin 19) is considered a promising biomarker for diagnosing preeclampsia, little is known regarding the levels of CYFRA 21-1 during pregnancy. Here, we measured serum CYFRA 21-1 levels in women with an uneventful pregnancy and in women whose pregnancy was complicated by preeclampsia. Furthermore we evaluated whether maternal CYFRA 21-1 levels can be used to predict and/or diagnose preeclampsia. METHODS: Longitudinal, sequential blood samples were collected prospectively at seven predetermined visits during pregnancy. Maternal CYFRA 21-1 levels were measured in 50 women with an uneventful pregnancy (control group) and in 10 asymptomatic women whose pregnancy was later complicated by preeclampsia (PE_long group). In addition, CYFRA 21-1 levels were measured from a single sample collected from a separate group of 50 pregnant women with symptomatic preeclampsia (PE_state group). RESULTS: The CYFRA 21-1 levels were significantly higher in the PE_state group compared to the control group (p < 0.001). In the PE_long group, CYFRA 21-1 levels were lower from gestational week 11 through 17, but were higher than the control group from gestational weeks 18 through 36. Out of the ROC curves that were calculated to investigate the predictive and diagnostic properties of CYFRA 21-1 levels for preeclampsia, the ROC curve for diagnosing preeclampsia in gestational week 28-32 showed the largest AUC of 0.92, at a cut-off point of 3.1 ng/ml, leading to sensitivity of 92 % and specificity of 80 %. CONCLUSIONS: The elevated serum levels of CYFRA 21-1 observed in both groups of women with preeclampsia may reflect endothelial damage and/or dysfunction. Our results suggest that maternal serum CYFRA 21-1 is a promising biomarker for diagnosing preeclampsia. Although its value for predicting the long-term occurrence of subsequent preeclampsia may be limited, our findings indicate a trend towards elevated maternal CYFRA 21-1 levels preceding the short-term occurrence of preeclampsia in asymptomatic women. Additional prospective longitudinal studies are needed in order to determine the value of measuring maternal serum CYFRA 21-1 in predicting preeclampsia.

Development of medians generators for the calculation of MoM for the first-trimester Down syndrome maternal serum markers.

The Down syndrome risk calculation software, Fast Screen pre I plus, from Thermo Fisher Scientific, converts the First-trimester maternal serum markers concentrations (PAPP-A and hCGß) into degrees of extreme (DoE). To meet the requirements of the French legislation as well as those of the certified biologists for Down syndrome screening, a conversion tool for DoE into multiple of the median (MoM), intermediate reference value for the screening, was developed. In absence of any median polynomial allowing to obtain MoM easily, the calculations were made first on the basis of the polynomials centiles from the software. The subsequent reviews of the risk algorithms showed the fragility of this approach based on the Gaussian hypothesis. Medians generators, calculated from the data of the Kryptor club's biologists, were established.