The cumulative incidence of neonatal metabolic acidemia after terminal bradycardia in the 2nd stage of labor: a survival-based model.

PURPOSE: The aim of the study was to estimate by a survival analysis model the hazard function (HF) for neonatal metabolic acidemia (MA) throughout the 2nd stage of labor (2STG) at the time of occurrence of a terminal bradycardia ≥ 10 min requiring expedited delivery, and the cumulative incidence function (CIF) for MA according with the duration of bradycardia stratified in 10-12 min and > 12 min. METHODS: Singleton pregnancies experiencing terminal fetal bradycardia requiring expedited delivery in the 2STG at 38 + 0-41 + 3 weeks and delivering in the year 2019, were identified. The presence of MA (pH < 7 and/or BE ≤ - 12 mmol/L) was determined based on the acid-base status in the umbilical artery cord blood. Survival analysis was used to assess the hazard function (HF) and the cumulative incidence function (CIF) for MA occurring after terminal fetal bradycardia, at the 2STG. RESULTS: Out of a non-consecutive population of 12,331 pregnancies, there were 52 cases that fit the inclusion criteria. Twenty-four (46.2%) of those develop MA. Abnormal quantitative pH values and the HF for MA correlated with the duration of 2STG at the time of bradycardia onset, but not with bradycardia duration. After 60 min of duration of 2STG, the HF (or instantaneous rate of failure) increased dramatically (from 1.2 to 20 about at 120 min). At paired duration of 2STG, a higher CIF was observed for the terminal bradycardia > 12 min. CONCLUSION: Forty-six percent of term fetuses with terminal bradycardia had MA at birth. Despite the low sensitivity and a non-significant association with quantitative pH values, the duration of terminal bradycardia in the 2STG is associated with a higher CIF for MA.

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

Reference charts for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord.

PURPOSE: To determine reference values for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord and to compare these values with standard umbilical Doppler pulsatility index curves from 23 to 40 gestational weeks. METHODS: A retrospective longitudinal cohort study was conducted between January 2014 and December 2017 in a tertiary referral hospital and included 62 pregnant women with isolated single umbilical artery (two-vessel cord) and 174 measurements. Only uncomplicated term pregnancies were included. A reference curve for umbilical Doppler pulsatility index was built up and compared with a standard curve commonly used for fetuses with three-vessel cord. RESULTS: Umbilical Doppler pulsatility index values were much lower than expected in cases with two-vessel cord compared to 3-vessel cord: mean of the regression equations was 1.02 ± 0.23 vs. 0.86 ± 0.19, respectively (p value < 0.001). This difference was quite constant across the gestational weeks considered, showing that the slopes of the two regressions were very similar. CONCLUSION: Reference curves for umbilical Doppler pulsatility index in two-vessel cord pregnancies were determined. Pulsatility index values were significantly different compared with those commonly used for three-vessel cord. Using lower reference values for umbilical pulsatility index in cases with two-vessel cord may allow a better identification of fetuses affected with intrauterine growth restriction, thus improving fetal surveillance.

Higher rate of early-onset preeclampsia in pregnancies following oocyte donation according to increasing maternal age.

OBJECTIVE: To assess the influence of maternal age on the incidence of early-onset preeclampsia requiring delivery before 34 weeks of gestation in pregnancies obtained after oocyte donation. METHODS: We carried out a prospective cohort analysis of 431 single and twin pregnancies, admitted to 3 Tertiary Referral Hospital in Northern Italy between 2008 and 2017. The rate of early-onset PE was calculated and stratified according to maternal age (from 30 to 49 years). A reference population of 11,197 single pregnancies collected prospectively at the first trimester of pregnancy in the same geographic area of Italy and in same hospitals was used to calculate the expected incidence of early-onset PE. RESULTS: In women who delivered after 24 weeks of gestation, the rate of early-onset PE was much higher in oocyte-donation pregnancies, reaching 6.7% (29/431), than the expected rate of 0.5% of the cohort of reference. The mean early PE rate was 4.1% (10/242) in singletons and 10.1% (19/189) in twin pregnancies. According to maternal age, the rate of early PE was 1.16% and 3.12% at 30 years, and 4.98% and 13.14% at 49 years in single and twin pregnancies obtained after oocyte donation, respectively. CONCLUSION: Pregnancies obtained after oocyte donation delivering after 24 weeks had a higher risk of early-onset PE requiring delivery before 34 weeks of gestation, than the general population. The risk is directly correlated with the increase of maternal age and is also higher in twin pregnancies.

Comparison of two "a priori" risk assessment algorithms for preeclampsia in Italy: a prospective multicenter study.

PURPOSE: To compare the performance of the algorithms proposed by the Fetal Medicine Foundation in 2012 and BCNatal in 2013 in an Italian population. METHODS: A multicentric prospective study was carried out which included pregnancies at 11-13 weeks' gestation from Jan 2014 through May 2017. Two previously published algorithms were used for the calculation of the "a priori" risk of preeclampsia (based on risk factors from medical history) in each individual. RESULTS: In a study population of 11,632 cases, 67 (0.6%) developed early preeclampsia and 211 (1.8%) developed late preeclampsia. The detection rates (95% CI) for early and late preeclampsia were 58.2% (45.5-70.2) vs. 41.8% (29.6-54.5) (p value < 0.05) and 44.1% (37.3-51.1) vs. 38% (31.3-44.8) (p value < 0.05) for the Fetal Medicine Foundation and BCNatal, respectively (at a 10% false positive rate). The associated risk was 1:226 and 1:198 (p value ns) for early PE, and 1:17 and 1:24 (p value ns) for late PE for the Fetal Medicine Foundation and BCNatal, respectively. CONCLUSIONS: The Fetal Medicine Foundation screening for preeclampsia at 11-13 weeks' gestation scored the highest detection rate for both early and late PE. At a fixed 10% false positive rate, the estimated "a priori" risks of both the Fetal Medicine Foundation and the BCNatal algorithms in an Italian population were quite similar, and both were reliable and consistent.

Untimely diagnosis of fetomaternal hemorrhage: what went wrong?

Fetomaternal hemorrhage (FMH) is an obstetrical challenge. It is defined as a passage of fetal blood into the maternal circulation or vice versa, which might complicate pregnancy or delivery. Most cases of acute and chronic FMH are idiopathic in origin and involve uncomplicated near-term pregnancies. Yet, due to the lack of universal screening, heterogeneous clinical presentation and insufficient clinicians awareness, in some cases FMH may present as immediate fetal compromise or even stillbirth as the most devastating consequence. We made a review of the literature of the FMH clinical cases of fetal/neonatal death in order to focus on the available diagnostic tools and their limitations. Cardiotocography, biophysical profile, middle cerebral artery peak systolic volume and current laboratory tests were studied and evaluated as diagnostic tools for FMH. International guidelines are needed to help clinicians make a prompt identification of FMH. Moreover, a standardized management protocol is essential in order to improve fetal-neonatal outcomes.

Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study.

OBJECTIVES: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. METHODS: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. RESULTS: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. CONCLUSIONS: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

Epigenetics Beyond Fetal Growth Restriction: A Comprehensive Overview.

Fetal growth restriction is a pathological condition occurring when the fetus does not reach the genetically determined growth potential. The etiology of fetal growth restriction is expected to be multifactorial and include fetal, maternal, and placental factors, the latter being the most frequent cause of isolated fetal growth restriction. Severe fetal growth restriction has been related to both an increased risk of perinatal morbidity and mortality, and also a greater susceptibility to developing diseases (especially cardio-metabolic and neurological disorders) later in life. In the last decade, emerging evidence has supported the hypothesis of the Developmental Origin of Health and Disease, which states that individual developmental 'programming' takes place via a delicate fine tuning of fetal genetic and epigenetic marks in response to a large variety of 'stressor' exposures during pregnancy. As the placenta is the maternal-fetal interface, it has a crucial role in fetal programming, such that any perturbation altering placental function interferes with both in-utero fetal growth and also with the adult life phenotype. Several epigenetic mechanisms have been highlighted in modulating the dynamic placental epigenome, including alterations in DNA methylation status, post-translational modification of histones, and non-coding RNAs. This review aims to provide a comprehensive and critical overview of the available literature on the epigenetic background of fetal growth restriction. A targeted research strategy was performed using PubMed, MEDLINE, Embase, and The Cochrane Library up to January 2022. A detailed and fully referenced synthesis of available literature following the Scale for the Assessment of Narrative Review Articles guidelines is provided. A variety of epigenetic marks predominantly interfering with placental development, function, and metabolism were found to be potentially associated with fetal growth restriction. Available evidence on the role of environmental exposures in shaping the placental epigenome and the fetal phenotype were also critically discussed. Because of the highly dynamic crosstalk between epigenetic mechanisms and the extra level of complexity in interpreting the final placental transcriptome, a full comprehension of these phenomenon is still lacking and advances in multi-omics approaches are urgently needed. Elucidating the role of epigenetics in the developmental origins of health and disease represents a new challenge for the coming years, with the goal of providing early interventions and prevention strategies and, hopefully, new treatment opportunities.

Fetal disseminated intravascular coagulopathy, hydrops and massive umbilical vein thrombosis consequence of a rare placental condition: multifocal chorangiomatosis.

Purpose: Villous capillary lesions are rare abnormal placental developmental conditions which include chorangiosis, chorangiomatosis, chorangioma and a rare variant of the latter called multiple chorangioma syndrome. The causes of villous capillary lesion are not completely clear but appear to involve excessive angiogenesis. MATERIALS AND METHODS: In this paper we start illustrating our experience of multifocal chorangiomatosis with the newborn affected by massive umbilical vein thrombosis, disseminated intravascular coagulopathy and hydrops, going to a literature review of cases available.Results: Two other similar cases have been previously published in literature. Comparing clinical characteristics and fetal outcomes, we confirm the association with unfavorable neonatal outcome mentioned in literature. Our case is the first characterized by severe hemolytic anemia, thrombocytopenia, heart congestion with the overlap of disseminated intravascular coagulopathy and massive umbilical vein thrombosis and congenital anomalies. CONCLUSIONS: Our clinical case and the review of literature highlight how multifocal chorangiomatosis, within the three subgroups identified, is the rarer form with distinct placental features and the worst outcomes for neonates. No cases of multifocal chorangiomatosis have never been described prenatally and, for further studies, could be reasonable investigate the involvement of some growth factors like vascular endothelial growth factor and placental growth factor that could lead to a detection of a subgroup of patient at higher risk to manifest placental vascular lesions and the follow fetal and maternal complications.

Prenatal Diagnosis and Postnatal Outcomes of Left Brachiocephalic Vein Abnormalities: Systematic Review.

Abnormalities of the left brachiocephalic vein (LBCVA) are rare and poorly studied prenatally. An association with congenital heart defects (CHD), extracardiac and genetic abnormalities was described. The aim of our study was to estimate the rate and summarize the available evidence concerning prenatal diagnosis, associated anomalies, and outcomes of these anomalies. A systematic literature review was carried out selecting studies reporting on prenatal diagnosis of LBCVA, including unpublished cases from our experience. Frequencies were pooled from cohort studies to calculate prenatal incidence. Pooled proportions were obtained from all the studies including rates of associated CHD, extracardiac or genetic abnormalities and neonatal outcomes. The search resulted in the selection of 16 studies with 311 cases of LBCVA, with an incidence of 0.4% from six cohort studies. CHD occurred in 235/311 (75.6%) fetuses: 23 (7.4%) were major in cases of double, retroesophageal or subaortic course and 212 (68.2%) were minor in cases of absence (always associated with a persistent left superior vena cava) or intrathymic course. Data on other associated outcomes were scarce showing rare extracardiac anomalies (3.5%), rare genetic abnormalities (RASopathies and microdeletions associated with the retroesophageal course), and neonatal outcomes favorable in most cases, particularly in intrathymic forms.

Evaluating the Effectiveness of Pharmacological Strategies and Further Measures for Pain Relief during Hysterosonosalpingography: A Systematic Review.

This systematic review aims to evaluate the effectiveness of pharmacological and non-pharmacological strategies for pain relief in women during contrast-enhanced ultrasound for the assessment of tubal patency and uterine disease, compared with placebo or no intervention. In December 2021, we searched the electronic databases (Pubmed, Embase, Sciencedirect, the Cochrane library and Clinicaltrials.gov) without date restriction: We identified 10 randomized control trials (RCTs) (2098 women) eligible for this systematic review, after applying our inclusion and exclusion criteria. Among these, five studies compared the use of painkillers with the placebo, two studies compared different catheter positions in the cervix or in the uterine cavity, and two others considered different temperatures of the contrast medium, as a method to reduce pain. Topical lidocaine applied before the procedure may be associated with effective pain relief during hysterosonography, though the quality of this evidence is low. New echogenic contrast agents and their temperature at 37 °C ensure a less painful procedure. There is insufficient evidence to draw conclusions on the efficacy of other analgesics or strategies.

Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia.

OBJECTIVE: To determine the performance of screening for late pre-eclampsia (PE) by maternal characteristics, uterine artery Doppler and a set of biochemical markers at 11 + 0 to 13 + 6 weeks' gestation. METHODS: Prospectively enrolled women at 11 + 0 to 13 + 6 weeks. Maternal characteristics, highest UtA pulsatility index and serum placental biomarkers including pregnancy-associated plasma protein-A, placental growth factor, soluble fms-like tyrosine kinase 1, P-selectin and neutrophil gelatinase-associated lipocalin were recorded. RESULTS: The rate of PE was 2.5% (13/528). Four (0.8%) had severe PE. A combined screening model that included placental growth factor, soluble fms-like tyrosine kinase 1 and neutrophil gelatinase-associated lipocalin could detect 77% of PE at a 10% false-positive rate. Mean risk for mild PE was 8.8% ± 6.4, mean risk for severe PE was 38.6% ± 4.3. Mean risk for controls was 2% ± 4.1. CONCLUSION: This combination of maternal biochemical variables in the first trimester can detect a consistent number of late PE. Further studies on a new and independent series of data could confirm the presented results.

Prospective evaluation of ultrasound and biochemical-based multivariable models for the prediction of late pre-eclampsia.

OBJECTIVE: Prospective assignment at 11 + 0 to 13 + 6 weeks of risk for late pre-eclampsia (PE) using eight logistic regression-based statistical models. METHODS: Five hundred and fifty-four pregnancies. Uterine artery pulsatility index, parity, body mass index, mean arterial pressure, pregnancy-associated plasma protein-A, free ß-human chorionic gonadotrophin and maternal age, were combined to obtain 'a posteriori risk of PE'. RESULTS: We observed 39 cases (7%) of late PE. There were 12 cases of severe PE and 27 of mild PE. According to the models used, the estimated detection rate ranged from 38.5% to 84.6% with a false-positive rate of 10%. The median risk ratio (estimated median risk of PE in affected pregnancies divided by estimated risk of PE in unaffected pregnancies) ranged between 1.66 and 7.61. The most reproducible biochemical-based model was a mixed model encompassing maternal history and pregnancy-associated plasma protein-A. CONCLUSION: Some of the multivariable models drawn from the literature accurately predicted the late PE occurrence. The failure of some models may be because of the population in question not bearing several of the risk factors used to generate the models proposed. An effective combined screening at first trimester for late PE seems possible.

Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop pre-eclampsia later in pregnancy: implications for screening.

OBJECTIVES: To determine the gene expression profile in chorionic villous samples (CVSs) of women destined to develop pre-eclampsia (PE). METHOD: Case-control study encompassing five women destined to develop PE [cases matched for gestational age with 30 controls]. We quantified mRNA expression on tissue samples from CVS of normal and PE patients. We then assessed mRNA expressions of cathepsin (CTSD), angiopoietin 2 (ANGPT2), interleukin 8, chemokine (C-X-C motif) ligand 10, neurokinin B (NKB), matrix metallopeptidase 9, major histocompatibility complex, class I, C (HLA-C)and human leukocyte antigen-G (HLA-G). Data were analyzed by nonparametric rank analysis. RESULTS: For all the mRNA species considered in this study, except CTSD and ANGPT2, all the mean observed ranks in the PE group were significantly altered compared with the rank expectation among controls. mRNA for NKB and HLA-C were the markers with the highest degree of aberration in PE, compared with those in controls. CONCLUSION: Our study has directly showed that gene expressions relating to trophoblastic cell invasion or utero-placental hemodynamic adaptation are altered in the first trimester trophoblasts that go on to develop PE later. These results posit the use of residual CVS as a possible screening method for PE.

Conservative methotrexate treatment of a scar pregnancy case: adding evidence to the evidence.

A single case of ultrasonographic-guided local injection of methotrexate for managing scar pregnancy is reported. The outcome was successful and had no side effects. The case was reported to increase the evidence supporting this type of management.

AUditive Direct in Utero Observation (AUDIO): A Randomized Controlled Trial for a Prenatal Demonstration of Fetal Hearing.

INTRODUCTION: The objective of this randomized controlled study was to demonstrate whether acoustic stimulation in utero is associated with fetal reactivity which is documentable by cardiotocography. MATERIALS AND METHODS: A monocentric randomized controlled trial was performed at a single university tertiary hospital between September 2016 and July 2017. This study was registered as a randomized clinical trial on clinicaltrail.gov (registration number NCT04622059). Unselected pregnancies at term of gestation were consecutively recruited for the purpose of this study. After 10 min of normal cardiotocography without accelerations (non-stress-test with a basal frequency between 110 and 150 beats/min, normal variability between 6 and 15 b/min, no accelerations, and no fetal movements), fetuses were randomized at a 1:1 ratio to either of the two groups. Fetuses in group A (n = 105) received acoustic stimulation after 10 min from the beginning of the CTG, whereas fetuses in group B received no stimulation (n = 105). The outcome variables investigated were the lapse of time between the beginning of the CTG and the occurrence of the first acceleration, and the lapse of time between the beginning of the CTG and the first fetal movement noticed. RESULTS: The lapse of time between the beginning of the CTG and the occurrence of the first acceleration was significantly shorter in the group with acoustic stimulation compared to the other group (14.87 ± 5.01 vs. 21.90 ± 6.94 min, p-value < 0.001 log-rank test). Similarly, the lapse of time between the beginning of the CTG and the occurrence of the first fetal movement was significantly shorter in group A compared to group B (17.77 ± 7.62 vs. 23.28 ± 7.61 min, p-value < 0.001, log-rank test). Fetal cardiac acceleration and the occurrence of a fetal movement during the first 20 min of the CTG were more frequently recorded in group A compared to group B (respectively, 15% vs. 5% and 20% vs. 8%). CONCLUSION: This RCT showed an early fetal reaction following auditive stimulus, documentable by cardiotocography. Further research is needed to investigate a possible role of acoustic stimulation in utero for the prenatal diagnosis of congenital hypoacusis.

Greater fetal crown-rump length growth with the use of in vitro fertilization or intracytoplasmic sperm injection conceptions after thawed versus fresh blastocyst transfers: secondary analysis of a prospective cohort study.

OBJECTIVE: To compare first-trimester fetal crown-rump length (CRL) measurements in pregnancies obtained after thawed blastocyst transfer versus fresh blastocyst transfer after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective longitudinal cohort study of CRL Z scores with adjustment for major confounders. SETTING: University-affiliated obstetrics, fetal medicine, and fertility units. PATIENT(S): Singleton gestations conceived via IVF/ICSI and fresh or thawed blastocyst transfer with ultrasound performed at 6-14 weeks of gestational age. INTEVENTION: None. MAIN OUTCOME MEASURE(S): CRL Z scores. RESULT(S): A total of 365 IVF/ICSI pregnancies were recruited (fresh: 161; thawed: 204). The mean CRL Z score at 6-14 weeks was significantly greater in thawed versus fresh transfers. Different growth trajectories between thawed and fresh transfers were detected: Mean CRL Z score was 0 at 65 days in fresh versus 80 days in frozen. Comparisons of both fresh and thawed transfers with reference values from the general population confirmed significantly lower CRL Z scores in both IVF/ICSI groups (P<.001). The risks of CRL <5th percentile in fresh versus thawed were, respectively 68% vs. 40% at 6 weeks and 2% vs. 1% at 14 weeks. A significant positive correlation between CRL Z scores and birth weight Z scores was found only for fresh transfers, not for thawed. CONCLUSION(S): At 6-14 weeks, thawed blastocyst transfers after IVF/ICSI conceptions present greater CRLs compared with fresh, and both IVF/ICSI groups show smaller CRLs than the general population. This effect is particularly evident before 9 weeks and it may favor birth weight difference of thawed versus fresh BT pregnancies.

Performance of messenger RNAs circulating in maternal blood in the prediction of preeclampsia at 10-14 weeks.

OBJECTIVE: The purpose of this study was to determine whether the combined distribution of a panel of cellular messenger RNA markers can detect preeclampsia long before onset. STUDY DESIGN: We compared blood at 10-14 weeks from 11 women who ultimately experienced preeclampsia with 88 matched control subjects. After multiples of the median conversion of all the markers, logistic regression was used to calculate the risk of the development of preeclampsia. RESULTS: Higher multiples of the median values than expected were found for endoglin, fms-related tyrosine kinase 1, and transforming growth factor-ß1. Lower multiples of the median values were found for placental growth factor and placental protein 13. Endoglin fms-related tyrosine kinase 1 and transforming growth factor-ß1 had the best discriminant power. Messenger RNA species provided independent contributions to the prediction of preeclampsia. In fact, 11 women with preeclampsia scored a median risk of 50% of experiencing preeclampsia. Control subjects scored a median risk of preeclampsia of 0.18%. The detection rate at a 5% false positive rate was 72.3%. CONCLUSION: The messenger RNA dosage in maternal blood would be a useful method for the calculation of the risk of the development of preeclampsia.

Circulating Nucleic Acids in Maternal Plasma and Serum in Pregnancy Complications: Are They Really Useful in Clinical Practice? A Systematic Review.

OBJECTIVE: A systematic review was carried out to summarize the available evidence to assess whether circulating nucleic acids in maternal plasma and serum (CNAPS) have the potential to serve as extra and independent markers for the prediction and/or progression monitoring of the most common and severe complications of pregnancy, including preeclampsia, intrauterine growth restriction, preterm delivery, morbidly adherent placenta, gestational diabetes, antiphospholipid syndrome, threatened abortion, intrahepatic cholestasis of pregnancy, and hyperemesis gravidarum. METHOD: A comprehensive literature search of the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases was conducted to identify relevant studies that included amounts of CNAPS in the abovementioned pregnancy complications. RESULTS: Eighty-three studies met the eligibility criteria. The vast majority of studies were conducted on the quantity of total circulating cell free DNA (cfDNA) and cell free fetal DNA (cffDNA), and some were conducted on messenger RNA (mRNA) species. A few studies have instead evaluated the cell free DNA fetal fraction (cfDNAff), but only in a limited number of pregnancy complications. Despite the growing interest and the abundance of the papers available, little information is available for other new CNAPS, including microRNA (miRNA), long noncoding RNA (lncRNA), mitochondrial DNA (mtDNA), and circular RNA. CONCLUSION: Due to the heterogeneity of the populations enrolled, the scarcity of the studies that adjusted the CNAPS values for possible confounding factors, and the difficulty in interpreting the published data, no conclusion regarding the statistical robustness and clinical relevance of the data can be made at present. If assayed at the third trimester, the CNAPS have, however, shown better performance, and could be used in populations already at risk of developing complications as suggested by the presence of other clinical features. Other CNAPS, including miRNA, are under investigation, especially for the screening of gestational diabetes mellitus, but no data about their clinical utility are available. Circulating DNA (cfDNA, cffDNA, and cfDNAff) and mRNA have not been properly evaluated yet, especially in patients asymptomatic early in pregnancy but who developed complications later, perhaps because of the high cost of these techniques and the availability of other predictors of pregnancy complications (biochemical, biophysical, and ultrasound markers). Therefore, from the analysis of the data, the positive predictive value is not available. As regards the new CNAPS, including miRNA, there are still no sufficient data to understand if they can be promising markers for pregnancy complications monitoring and screening, since CNAPS are statistically weak and expensive. It is reasonable to currently conclude that the use of the CNAPS in clinical practice is not recommended.