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A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.

Prenatal ultrasound (US) has been shown to overestimate the incidence of suspected fetal growth restriction (FGR) in gastroschisis cases. This is largely because of altered sonographic abdominal circumference (AC) measurements when comparing gastroschisis cases with population nomograms. Individualized Growth Assessment (IGA) evaluates fetal growth using serial US measurements that allow consideration of the growth potential for a given case. Our goal was to assess the utility of IGA for distinguishing normal and pathological fetal growth in gastroschisis cases.Pregnancies with prenatally diagnosed fetal gastroschisis were managed and delivered at a single academic medical center. US fetal biometry including head circumference (HC), abdominal circumference (AC), and femur diaphysis length (FDL), and neonatal measurements including birthweight and HC were collected and analyzed for 32 consecutive fetal gastroschisis cases with at least two 2nd and two 3rd trimester measurements. Second trimester growth velocities were compared to a group of 118 non-anomalous fetuses with normal neonatal growth outcomes. Gastroschisis cases were classified into groups based on fetal growth pathology score (FGPS9) patterns. Agreement between IGA (FGPS9) and serial conventional estimated fetal weight (EFW) measurements for determining growth pathology was evaluated. Neonatal size outcomes were compared between conventional birthweight classifications for determining small for gestational age (SGA) and IGA Growth Potential Realization Index (GPRI) for weight and head circumference measurements.Fetal growth pathology score (FGPS9) measurements identified three in-utero growth patterns: no growth pathology, growth restriction and recovery, and progressive growth restriction. In the no growth pathology group (We present the first study using IGA to evaluate normal and pathological fetal growth in prenatally diagnosed gastroschisis cases. IGA was able to delineate two 3rd trimester growth pathology patterns - one with persistent growth restriction and another with in-utero growth recovery. Further validation of these initial findings with larger cohorts is warranted.

To investigate factors associated with positive postpartum depression (PPD) screen in pregnancies complicated by fetal congenital cardiac anomaly. We reviewed all records of pregnancies complicated by fetal congenital cardiac anomaly receiving prenatal, intrapartum and postpartum care at our single center, October 2016-October 2019. Maternal, obstetric, and neonatal data were compared between women with and without a positive PPD screen at the 6-week postpartum visit. Out of 415 women referred for fetal congenital cardiac anomaly, 86 women had complete inclusion criteria. Twenty-four women (28%) had a positive PPD screen. The frequencies of planned future infant surgery (73.9 vs. 26.2%, p = 0.01) and neonatal death prior to postpartum visit (12.5 vs. 0%, p = 0.02) were significantly higher among women with a positive PPD screen. In pregnancies complicated by fetal congenital cardiac anomaly, mothers of infants with planned future surgery or neonatal death are at significant risk for postpartum depression.

Introduction: In fetuses with hypoplastic left-heart syndrome (HLHS), maternal hyperoxygenation (MHO) may aid risk stratification. We hypothesized that pulmonary vein (Pvein) velocity time integral (VTI) change with MHO would more reliably identify neonates who undergo emergent atrial septoplasty (EAS) than changes in pulmonary arterial pulsatility index (PA PI). Methods: Fetuses with HLHS who underwent MHO testing at our institution between 2014 and 2019 were identified. Data were reviewed in a blinded, retrospective manner. Pvein VTI ratio (prograde:retrograde) was calculated. The primary outcome was neonatal EAS. Results: Twenty-seven HLHS fetuses underwent MHO, and 5 (19%) underwent EAS. Without MHO, a Pvein VTI ratio Discussion/Conclusion: Addition of MHO appears to improve the diagnostic ability of the Pvein VTI ratio to identify HLHS fetuses who undergo EAS. The Pvein VTI ratio change may more accurately identify fetuses who undergo EAS than change in PA PI and has less interobserver variability.

Purpose of review Congenital diaphragmatic hernia (CDH) is a structural birth defect that results in significant neonatal morbidity and mortality. CDH occurs in 2-4 per 10 000 pregnancies, and despite meaningful advances in neonatal intensive care, the mortality rate in infants with isolated CDH is still 25-30%. In this review, we will present data on the molecular underpinnings of pathological lung development in CDH, prenatal diagnosis, and prognostication in CDH cases, existing fetal therapy modalities, and future directions. Recent findings Developments in the prenatal assessment and in-utero therapy of pregnancies complicated by congenital diaphragmatic hernia are rapidly evolving. Although ultrasound has been the mainstay of prenatal diagnosis, fetal MRI appears to be an increasingly important modality for severity classification. While fetal endoscopic tracheal occlusion (FETO) may have a role in the prenatal management of severe CDH cases, it is possible that future therapeutic paradigms will incorporate adjunct medical interventions with either stem cells or sildenafil in order to address the vascular effects of CDH on the developing lung. Summary Both animal and human data have shown that the pathophysiological underpinnings of CDH are multifactorial, and it appears that future prenatal assessments and therapies will likely be as well.

INTRODUCTION The clinical importance of mass effect from congenital lung masses on the fetal heart is unknown. We aimed to report cardiac measurements in fetuses with congenital lung masses and to correlate lung mass severity/size with cardiac dimensions and clinical outcomes. METHODS Cases were identified from our institutional database between 2009 and 2016. We recorded atrioventricular valve (AVVz) annulus dimensions and ventricular widths (VWz) converted into z scores, ratio of aortic to total cardiac output (AoCO), lesion side, and congenital pulmonary airway malformation volume ratio (CVR). Respiratory intervention (RI) was defined as intubation, extracorporeal membrane oxygenation (ECMO), or use of surgical intervention prior to discharge. RESULTS Fifty-two fetuses comprised the study cohort. Mean AVVz and VWz were below expected for gestational age. CVR correlated with ipsilateral AVVz (RS = -.59, P < .001) and ipsilateral VWz (-0.59, P < .001). Lower AVVz and AoCO and higher CVR were associated with RI. No patient had significant structural heart disease identified postnatally. CONCLUSION In fetuses with left-sided lung masses, ipsilateral cardiac structures tend to be smaller, but in our cohort, there were no patients with structural heart disease. However, smaller left-sided structures may contribute to the need for RI that affects a portion of these fetuses.

To investigate the effect of preterm gestational age (GA) on neonatal outcomes of gastroschisis and to compare the neonatal outcomes after spontaneous labor versus iatrogenic delivery both in the preterm and early term gestational periods.A retrospective study of prenatally diagnosed gastroschisis cases born at Loma Linda University Medical Center and Lucile Packard Children's Hospital (Loma Linda, CA) between January 2009 and October 2016. A total of 194 prenatally diagnosed gastroschisis cases were identified and included in the analysis. We compared infants delivered37 0/7 to those ≥37 0/7 weeks' gestation. Adverse neonatal outcome was defined as any of: sepsis, short bowel syndrome, prolonged ventilation, or death. Prolonged length of stay (LOS) was defined as ≥75th percentile value. Outcomes following spontaneous versus iatrogenic delivery were compared. Analyses were performed using chi-squared test or Fisher's exact test for categorical variables, and Student'sOne hundred and six neonates were born37 weeks and 88 at ≥37 weeks. Adverse outcome was statistically similar among those born37 weeks compared to ≥37 weeks (48 versus 34%,Neonates with gastroschisis delivered37 weeks had prolonged LOS whereas the rate of adverse neonatal outcomes was similar between those delivered preterm versus term. Neonates born after spontaneous preterm labor had a higher rate of bowel atresia compared to those born after planned iatrogenic preterm delivery.

To characterize factors associated with adverse neonatal outcomes in prenatally diagnosed omphalocele cases. Prenatally diagnosed omphalocele cases at a single referral center from 1 January 2009 to 31 December 2017 were retrospectively reviewed. Clinical variables and antenatal imaging measurements were collected. Associations between prenatal and neonatal characteristics and the adverse outcome of death or prolonged length of stay (LOS) were analyzed. Out of 63 fetal cases, 33 were live-born, > 50% had other anomalies, and neonatal mortality was 12%. Adverse outcomes were associated with neonatal variables, including lower median 1-min Apgar score, initial mechanical ventilation, and late-onset sepsis, but not approach to omphalocele closure. With multivariate analysis, death or prolonged LOS was associated only with low lung volumes by fetal MRI (OR 34 (3–422), p = 0.006). Low lung volumes by fetal MRI were associated with death or prolonged LOS in neonates with prenatally diagnosed omphalocele and may guide clinicians with counseling families.

Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care. The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes. Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE. The model derived in the Stanford cohort was highly significant (p = 3.9E–15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E–01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E–21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E–02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E–454, R = 0.92) and Detroit cohorts (p = 1.1.E–92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences. Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the “same” clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.

Fetal ventriculomegaly may occur in isolation or as part of a broader syndrome. We aimed to determine the added value of magnetic resonance imaging (MRI) for informing the pre-natal and postnatal care of pregnancies complicated by ventriculomegaly (VM). Retrospective analysis of all cases of prenatally diagnosed VM referred to the fetal center at Lucile Packard Children’s Hospital Stanford 1/1/2009–6/1/2014 were reviewed. Ultrasound (US) and MRI findings were reviewed, and the added yield of MRI evaluated. A total of 91 cases of fetal VM were identified and 74 (81%) underwent MRI. In 62/74 (84%) cases, additional CNS or non-CNS findings, not seen on US, were discovered on MRI, of which 58 were CNS-related. Forty-six (62%) of the additional findings were considered clinically relevant, of which 45 were CNS-related. Fetal MRI identifies additional, clinically relevant CNS and non-CNS findings in a majority of cases of VM following initial US.

BACKGROUND Plasma cell-free RNA (cfRNA) encompasses a broad spectrum of RNA species that can be derived from both human cells and microbes. Because cfRNA is fragmented and of low concentration, it has been challenging to profile its transcriptome using standard RNA-seq methods. METHODS We assessed several recently developed RNA-seq methods on cfRNA samples. We then analyzed the dynamic changes of both the human transcriptome and the microbiome of plasma during pregnancy from 60 women. RESULTS cfRNA reflects a well-orchestrated immune modulation during pregnancy: an up-regulation of antiinflammatory genes and an increased abundance of antimicrobial genes. We observed that the plasma microbiome remained relatively stable during pregnancy. The bacteria Ureaplasma shows an increased prevalence and increased abundance at postpartum, which is likely to be associated with postpartum infection. We demonstrated that cfRNA-seq can be used to monitor viral infections. We detected a number of human pathogens in our patients, including an undiagnosed patient with a high load of human parvovirus B19 virus (B19V), which is known to be a potential cause of complications in pregnancy. CONCLUSIONS Plasma cfRNA-seq demonstrates the potential to simultaneously monitor immune response and microbial infections during pregnancy.

Objective The aim of the study is to determine the prevalence of RASopathies in a polyhydramnios cohort selected by postnatal medical genetics evaluation. Methods In this retrospective study, we reviewed 622 pregnancies with polyhydramnios seen at Lucile Packard Children's Hospital between 2008-2017. The findings from 131 cases evaluated by Medical Genetics were included in our final analysis. Genetic testing information was extracted to determine the rate of chromosomal or single gene conditions focusing on the RASopathies. Additional variables collected were: maternal characteristics, ultrasound findings, and the severity and timing of diagnosis of polyhydramnios. Results Postnatal genetic testing or clinical examination identified a genetic disorder in 63 (48.1%) cases, more than half (n=33) of which had a single gene condition. Postnatal testing revealed an underlying RASopathy in 15 (11.5%) cases. An underlying RASopathy was significantly associated with the severity and timing of polyhydramnios (p Conclusion Focusing on a selected cohort postnatally evaluated by Medical Genetics, our study identified a chromosomal or genetic disorder in almost half of pregnancies complicated by polyhydramnios. Specifically, an underlying RASopathy was found in 11.5% of cases with 13/15 of these cases having additional ultrasound findings. This article is protected by copyright. All rights reserved.

Importance Bilateral renal agenesis is a rare congenital anomaly associated with poor prognosis. Objective The aims of this article are to review and summarize evidence on prenatal diagnosis and outcomes of bilateral renal agenesis. Evidence acquisition A search was undertaken using PubMed and ClinicalTrials.gov databases from January 1, 1998, to September 1, 2018. Search terms include "prenatal diagnosis" OR "outcomes" AND "bilateral renal agenesis." Search was limited to English language. Results Fetal ultrasonography is the primary imaging modality for prenatal diagnosis of fetal urogenital tract abnormalities. However, ultrasonography is limited by several factors; it is operator dependent and associated with small field of view, has limited soft-tissue acoustic contrast, and is also influenced by patient habitus and fetal position. Color Doppler ultrasonography can be used as an adjunct to exclude bilateral renal agenesis by visualizing renal arteries. In the literature, prenatal magnetic resonance imaging has been reported to be equal to or superior to prenatal ultrasonography. Bilateral renal agenesis with oligohydramnios/anhydramnios is associated with a poor prognosis; perinatal death occurs secondary to pulmonary hypoplasia in the majority of cases. Conclusions Ultrasonography in combination with color Doppler ultrasonography permits the fetal urinary tract to be assessed in the first and early second trimester of gestation. The magnetic resonance imaging can be used as a complementary adjunctive modality in equivocal or inconclusive ultrasonographic findings.

BACKGROUND Our goal was to develop an approach that can systematically identify potential associations between medication prescribed in pregnancy and spontaneous preterm birth (sPTB) by mining large administrative "claims" databases containing hundreds of medications. One such association that we illustrate emerged with antiviral medications used for herpes treatment. METHODS IBM MarketScan® databases (2007-2016) were used. A pregnancy cohort was established using International Classification of Diseases (ICD-9/10) codes. Multiple hypothesis testing and the Benjamini-Hochberg procedure that limited false discovery rate at 5% revealed, among 863 medications, five that showed odds ratios (ORs)

OBJECTIVES To develop a machine-learning (ML) model for prediction of shoulder dystocia (ShD) and to externally validate the model's predictive accuracy and potential clinical efficacy in optimizing the use of Cesarean delivery in the context of suspected macrosomia. METHODS We used electronic health records (EHR) from the Sheba Medical Center in Israel to develop the model (derivation cohort) and EHR from the University of California San Francisco Medical Center to validate the model's accuracy and clinical efficacy (validation cohort). Subsequent to application of inclusion and exclusion criteria, the derivation cohort included 686 singleton vaginal deliveries, of which 131 were complicated by ShD, and the validation cohort included 2584 deliveries, of which 31 were complicated by ShD. For each of these deliveries, we collected maternal and neonatal delivery outcomes coupled with maternal demographics, obstetric clinical data and sonographic fetal biometry. Biometric measurements and their derived estimated fetal weight were adjusted (aEFW) according to gestational age at delivery. A ML pipeline was utilized to develop the model. RESULTS In the derivation cohort, the ML model provided significantly better prediction than did the current clinical paradigm based on fetal weight and maternal diabetes: using nested cross-validation, the area under the receiver-operating-characteristics curve (AUC) of the model was 0.793 ± 0.041, outperforming aEFW combined with diabetes (AUC = 0.745 ± 0.044, P = 1e-16 ). The following risk modifiers had a positive beta that was > 0.02, i.e. they increased the risk of ShD: aEFW (beta = 0.164), pregestational diabetes (beta = 0.047), prior ShD (beta = 0.04), female fetal sex (beta = 0.04) and adjusted abdominal circumference (beta = 0.03). The following risk modifiers had a negative beta that was

Objective To evaluate the utility of fetal lung mass imaging for predicting neonatal respiratory distress. Method Pregnancies with fetal lung masses between 2009 and 2014 at a single center were analyzed. Neonatal respiratory distress was defined as: Intubation and mechanical ventilation at birth, surgery before discharge, or ECMO. The predictive utility of the initial as well as maximal lung mass volume and congenital pulmonary airway malformation (CPAM) volume ratio (CVR) by US and MRI was analyzed. Results 47 fetal lung mass cases were included; of those, 8 (17%) had respiratory distress. The initial US was performed at similar gestational ages in pregnancies with and without respiratory distress (26.4 + 5.6 vs. 22.3 + 3 weeks, p = 0.09); however, those with respiratory distress had higher CVR at that time (1.0 vs. 0.3, p = 0.01). The strongest predictors of respiratory distress were maximal volume >24.0 cm3 by MRI (100% sensitivity, 91% specificity, 60% PPV, 100% NPV), and maximal volume >34.0 cm3 by US, (100% sensitivity, 85% specificity, 54% PPV, 100% NPV). Conclusion US and MRI parameters can predict neonatal respiratory distress, even when obtained before 24 weeks. Third trimester parameters demonstrated the best positive predictive value.

To assess the accuracy of different sonographic estimated fetal weight (EFW) cutoffs, and combinations of EFW and biometric measurements for predicting small for gestational age (SGA) in fetal gastroschisis.Gastroschisis cases from two centers were included. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated for different EFW cutoffs, as well as EFW and biometric measurement combinations.Seventy gastroschisis cases were analyzed. An EFW10% had 94% sensitivity, 43% specificity, 33% PPV and 96% NPV for SGA at delivery. Using an EFW cutoff of5% improved the specificity to 63% and PPV to 41%, but decreased the sensitivity to 88%. Combining an abdominal circumference (AC) or femur length (FL) z-score less than -2 with the total EFW improved the specificity and PPV but decreased the sensitivity.A combination of a small AC or FL along with EFW increases the specificity and PPV, but decreases the sensitivity of predicting SGA.

This work presents the workflow for generating single cell transcriptomes derived from primary human uterine and cervical tissue obtained during planned cesarean hysterectomies. In total, a catalogue of 310 single cell transcriptomes are obtained, cell types present in these biopsies are inferred, and specific genes defining each of the cellular types present in the tissue are identified. Further validation of the inferred cell identity is also demonstrated via meta-analysis of independent repositories in literature generated by bulk sequenced data of fluorescence-activated cell sorting sorted cells.

Objective We compared the prevalence of and risk factors for stillbirth and live birth at periviable gestational age (20–25 weeks). Study Design This is a cohort study of 2.5 million singleton births in California from 2007 to 2011. We estimated racial–ethnic prevalence ratios and used multivariable logistic regression for risk factor comparisons. Results In this study, 42% of deliveries at 20 to 25 weeks' gestation were stillbirths, and 22% were live births who died within 24 hours. The prevalence of delivery at periviable gestation was 3.4 per 1,000 deliveries among whites, 10.9 for blacks, 3.5 for Asians, and 4.4 for Hispanics. Nonwhite race–ethnicity, lower education, uninsured status, being U.S. born, older age, obesity, smoking, pre-pregnancy hypertension, nulliparity, interpregnancy interval, and prior preterm birth or stillbirth were all associated with increased risk of both stillbirth and live birth at 20 to 25 weeks' gestation, compared with delivery of a live birth at 37 to 41 weeks. Conclusion Inclusion of stillbirths and live births in studies of deliveries at periviable gestations is important.

Purpose of review To examine updates in fetal spina bifida surgical repair, as well as promising results emerging from translational medicine. Recent findings Although the Management of Myelomeningocele Study sponsored by the National Institutes of Health helped establish the neonatal benefits of prenatal spina bifida repair via uterine hysterotomy, also known as 'open' fetal surgery, fetoscopic approaches may yield better maternal and obstetric outcomes. Summary Spina bifida is a severe congenital malformation associated with significant neonatal and childhood morbidity and mortality. Although 'open' fetal spina bifida repair has become the standard prenatal surgical approach due to proven neonatal benefit, this approach is associated with significant maternal and obstetric risks. Recent developments from multidisciplinary clinical and translational research have highlighted the potential for novel fetoscopic surgical approaches to decrease maternal morbidity and reduce obstetric risks. Moreover, novel stem cell therapies coupled with in-utero medical approaches targeting the pathophysiological pathways associated with spina bifida are likely to make additional significant impact.

OBJECTIVE To assess pregnant women's preferences regarding prenatal testing for microdeletion and microduplication conditions, and to identify what factors might influence their decisions. METHOD A written questionnaire was administered to pregnant women presenting for prenatal ultrasound. The questionnaire described the salient features of six microdeletion and microduplication syndromes of varying penetrance. Women were asked to indicate whether they would choose to test for each condition via an invasive diagnostic procedure, a non-invasive blood test, or not at all. Demographic and obstetrical data were also obtained. RESULTS One hundred twenty-four women returned the questionnaire (response rate 89.2%). More than half of women (50.8%) made distinctions between conditions and would choose a mixture of invasive testing, non-invasive testing, and no testing, depending on the condition. Testing preferences differed based on penetrance and features of the conditions. Prior prenatal testing, ethnicity, and education level were significantly associated (p

Objective To estimate the incremental yield of detecting copy number variants (CNVs) by genomic microarray over karyotyping in fetuses with increased nuchal translucency (NT) diagnosed by first-trimester ultrasound. Methods This was a systematic review conducted in accordance with PRISMA criteria. We searched PubMed, Ovid MEDLINE and Web of Science for studies published between January 2009 and January 2015 that described CNVs in fetuses with increased NT, usually defined as ≥ 3.5 mm, and normal karyotype. Search terms included: fetal or prenatal, nuchal translucency or cystic hygroma or ultrasound anomaly, array comparative genomic hybridization or copy number variants, with related search terms. Risk differences were pooled to estimate the overall and stratified microarray incremental yield using RevMan. Quality assessment of included studies was performed using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2) checklist. Results Seventeen studies met the inclusion criteria for analysis. Meta-analysis indicated an incremental yield of 5.0% (95% CI, 2.0–8.0%) for the detection of CNVs using microarray when pooling results. Stratified analysis of microarray results demonstrated a 4.0% (95% CI, 2.0–7.0%) incremental yield in cases of isolated NT and 7.0% (95% CI, 2.0–12.0%) when other malformations were present. The most common pathogenic CNVs reported were 22q11.2 deletion, 22q11.2 duplication, 10q26.12q26.3 deletion and 12q21q22 deletion. The pooled prevalence for variants of uncertain significance was 1%. Conclusion The use of genomic microarray provides a 5.0% incremental yield of detecting CNVs in fetuses with increased NT and normal karyotype. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

A successful fetal center provides a complete continuum of care for complex fetal patients, expectant mothers, and families. Ongoing communication among community obstetricians, pediatricians, maternal-fetal medicine physicians, neonatologists, and other pediatric specialists is critical to provide comprehensive prenatal counseling and establish a supportive care team for families before and after the birth of their child. This case reveals the role of a fetal center in planning for the delivery and resuscitation of conjoined twins and their subsequent postnatal care.

To examine associations with morbidly adherent placenta (MAP) among women with placenta previa.Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236,714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls.In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ⩾95th percentile (⩾2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ⩾95th percentile (⩾1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ⩾2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively).Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa.

Objectives Neonates with gastroschisis are often small for gestational age (SGA) based on population nomograms. Our objective was to evaluate the effect of SGA on perinatal and neonatal outcomes in cases of gastroschisis. Methods This is a retrospective study of neonates with prenatally diagnosed gastroschisis from two academic centers between 2008 and 13. Perinatal and neonatal outcomes of neonates with SGA at birth were compared with appropriate-for-gestational-age (AGA) neonates. The primary composite outcome was defined as any of the following: neonatal sepsis, short bowel syndrome at discharge, prolonged mechanical ventilation (upper quartile for the cohort), bowel atresia or death. Results We identified 112 cases of gastroschisis, 25 of whom (22%) were SGA at birth. There were no differences in adverse peripartum outcomes between SGA and AGA infants. No difference was found in the primary composite neonatal outcome (52% vs 36%, p = 0.21), but SGA infants were more likely to have prolonged mechanical ventilation (44% vs 22%, p = 0.04) and prolonged length of stay (LOS) (52% vs 22%, p = 0.007). After adjusting for GA at delivery, SGA remained associated with prolonged LOS (OR = 4.3, CI: 1.6–11.8). Conclusion Among infants with gastroschisis, SGA at birth is associated with a fourfold increase in odds for prolonged LOS, independent of GA. © 2015 John Wiley & Sons, Ltd.

Purpose of study Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. Methods used Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. Summary of results Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24–48 h were 53 mcmol/l and 62 mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3 months and 5 months. The patients show normal development at ages 7 and 3 years. Conclusion Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Objective The objective of this study was to evaluate whether weekly administration of 17 α-hydroxyprogesterone caproate (17-OHPC) increases the number of women who achieve 34 weeks of gestation after preterm premature rupture of membranes (PPROM). Study Design We conducted a multicenter double-blind, randomized controlled trial of 17-OHPC versus placebo among women with PPROM. Women with singleton pregnancy, clinically confirmed PPROM, and without evidence of active infection or major fetal malformation between 240/7 and 320/7 weeks of pregnancy were offered enrollment. Women received weekly injections of 17-OHPC versus placebo until 340/7 weeks of gestation or delivery. The remainder of care was per hospital protocol. The primary outcome was achievement of 34 weeks of gestation. Secondary outcomes included length of latency and maternal and fetal outcomes. Results In this study, 21 women were enrolled. Eleven women received placebo and 10 received 17-OHPC. The study was closed prematurely secondary to poor enrollment. None of the women remained pregnant until 34 weeks of gestation. The median latency periods were 8 and 14.5 days for the placebo and 17-OHPC groups, respectively (p = 0.14). There were no differences in maternal or neonatal outcomes. Conclusion We did not identify any benefit from administration of 17-OHPC in pregnancies complicated by PPROM.

Cesarean delivery is one of the most common surgeries performed in the United States. In 2012, over 1.2 million cesarean deliveries were performed, accounting for 32.8% of all deliveries.1 Cesarean delivery has been implicated as an important explanatory factor for increasing rates of maternal morbidity, which includes venous thromboembolism, shock, and hemorrhage.2 As a consequence, multiple large-scale initiatives have been promoted by leading obstetric figures and organizations to reduce rates of maternal morbidity.3–5 Postoperative length of stay (LOS) after nonobstetric surgery has been identified as an important quality indicator of inpatient care.6–8 LOS after cesarean delivery may also be an important metric for evaluating the quality of peripartum and postpartum obstetric care. Unfortunately, studies investigating risk factors associated with prolonged LOS after a cesarean delivery are lacking. Such data could assist ongoing efforts aimed at reducing maternal morbidity after cesarean delivery and could be useful for evaluating postcesarean LOS as a quality measure related to obstetric practice. The primary aim of this study was to identify risk factors for prolonged postpartum LOS after cesarean delivery. Moreover, we sought to analyze the contribution of potentially modifiable risk factors on prolonged LOS to highlight areas where improvements in perioperative care could be made. We also performed a secondary analysis to identify risk factors for prolonged LOS for the entire delivery hospitalization period including the intrapartum period.

Objective Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in-situ hybridization (FISH), in the setting of prenatally-diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting. Methods Articles in PubMed, EMBASE and Web of Science databases from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: ‘array comparative genomic hybridization’, ‘copy number variants’ and ‘fetal congenital heart defects’. Articles regarding karyotyping or 22q11 deletion only were excluded. Results Thirteen publications (including 1131 cases of CHD) met the inclusion criteria for the analysis. Meta-analysis indicated an incremental yield of 7.0% (95% CI, 5.3–8.6%) for the detection of CNVs using aCGH, excluding aneuploidy and 22q11 microdeletion cases. Subgroup results showed a 3.4% (95% CI, 0.3–6.6%) incremental yield in isolated CHD cases, and 9.3% (95% CI, 6.6–12%) when extracardiac malformations were present. Overall, an incremental yield of 12% (95% CI, 7.6–16%) was found when 22q11 deletion cases were included. There was an additional yield of 3.4% (95% CI, 2.1–4.6%) for detecting variants of unknown significance (VOUS). Conclusions In this review we provide an overview of published data and discuss the benefits and limitations of using aCGH. If karyotyping and 22q11 microdeletion analysis by FISH are normal, using aCGH has additional value, detecting pathogenic CNVs in 7.0% of prenatally diagnosed CHD, with a 3.4% additional yield of detecting VOUS. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Multicystic dysplastic kidney (MCDK) is one of the most common anomalies detected by prenatal ultrasound. Our objective was to identify factors associated with severe adverse neonatal outcomes of prenatally diagnosed MCDK STUDY DESIGN: A retrospective review of prenatally diagnosed MCDK (1 January 2009 to 30 December 2014) from a single academic center was conducted. The primary outcome was death or need for dialysis among live-born infants. Associations between prenatal characteristics and outcome were analyzed by Fisher's exact test and Mann-Whitney test.A total of 53 cases of prenatally suspected MCDK were included, of which 46 cases were live-born and confirmed postnatally (38 survivors, 8 non-survivors). Prenatally diagnosed extrarenal anomalies, bilateral MCDK, contralateral renal anomalies, and anhydramnios were significantly associated with death or need for dialysis (all p 0.0001).Prenatally identified findings are associated with adverse neonatal outcome, and can guide counseling and management planning. In the absence of significant associated findings, prenatally diagnosed unilateral MCDK has a benign neonatal course.

Background Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome. Objective The recent availability of a highly multiplexed platform affording the simultaneous measurement of 1310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes. Study Design Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7–14 weeks), second (15–20 weeks), and third (24–32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term. Results An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 × 10–14, R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 × 10–3, R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age. Conclusion Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy.

BackgroundPrenatal diagnosis in pregnancies at risk of single-gene disorders is currently performed using invasive methods such as chorionic villus sampling and amniocentesis. This is in contrast with screening for common aneuploidies, for which noninvasive methods with a single maternal blood sample have become standard clinical practice.MethodsWe developed a protocol for noninvasive prenatal diagnosis of inherited single gene disorders using droplet digital PCR (ddPCR) from circulating cell-free DNA (cfDNA) in maternal plasma. First, the amount of cfDNA and fetal fraction are determined using a panel of Taqman assays targeting high-variability SNPs. Second, the ratio of healthy and diseased alleles in maternal plasma are quantified using Taqman assays targeting the mutations carried by the parents. Two validation approaches of the mutation assay are presented.ResultsWe collected blood samples from 9 pregnancies at risk for different single gene disorders including common conditions and rare metabolic disorders. We measured cases at risk of hemophilia, ornithine transcarbamylase deficiency, cystic fibrosis, β-thalassemia, mevalonate kinase deficiency, acetylcholine receptor deficiency and DFNB1 nonsyndromic hearing loss. We correctly differentiated affected and unaffected pregnancies (2 affected, 7 unaffected), confirmed by neonatal testing. We successfully measured an affected pregnancy as early as week 11, and with a fetal fraction as low as 3.7±0.3%.ConclusionOur method detects single nucleotide mutations of autosomal recessive diseases as early as the first trimester of pregnancy. This is of importance for metabolic disorders where early diagnosis can affect management of the disease and reduce complications and anxiety related to invasive testing.

To compare the efficacy of oral misoprostol to vaginal dinoprostone for labor induction in nulliparous women.Admissions for labor induction from January 2008 to December 2010 were reviewed. Patients receiving oral misoprostol were compared with those receiving vaginal dinoprostone. The primary outcome was time from induction agent administration to vaginal delivery. Secondary outcomes included vaginal delivery within 24 h, mode of delivery and maternal and fetal outcomes.A total of 680 women were included: 483 (71%) received vaginal dinoprostone and 197 (29%) received oral misoprostol. Women who received oral misoprostol had a shorter interval to vaginal delivery (27.2 vs 21.9 h, P0.0001) and were more likely to deliver vaginally in24 h (47% vs 64%, P=0.001). There was no increase in the rate of cesarean delivery or adverse maternal or neonatal outcomes.Labor induction with oral misoprostol resulted in shorter time to vaginal delivery without increased adverse outcomes in nulliparous women.

To investigate the association between small-for-gestational age (SGA) and neurocognitive impairment at 2 years of corrected age among infants born at preterm gestational ages.A secondary analysis of a prospectively conducted NICHD/Maternal-Fetal Medicine Units BEAM trial. Non-anomalous pregnancies delivered before 37 weeks of gestation were included in the analysis. Neurocognitive outcomes at 2 years of corrected age were compared between infants who were SGA (10% for gestational age) and those appropriately grown (AGA). The primary outcome was a severe or moderate neurocognitive impairment at 2 years of corrected age among survivors, defined as either mental (MDI) or psychomotor (PDI) developmental index score70 for severe and85 for moderate impairment.Of 2299 preterm neonates 67 (3%) were SGA. SGA infants were more often twin pregnancies (31% vs 17%, P=0.003) and delivered more often by cesarean section (63% vs 40%, P0.001) at similar gestational ages (30.0±2.6 vs 29.5±2.8 weeks, P=0.11). At 2 years of corrected age, SGA and AGA survivors had similar rates of neurocognitive impairment (MDI70: 18% vs 18%, P=1.0; MDI85: 44% vs 46%, P=0.96; PDI70: 20% vs 15%, P=0.51; PDI85: 40% vs 34%, P=0.48).In this cohort, SGA at preterm gestational ages was associated with similar rates of neurocognitive impairment at two years of corrected age among surviving infants.

Background Limited understanding exists of risk factors for PPH post-vaginal delivery. Objective To identify risk factors for PPH post-vaginal delivery within a contemporary obstetric cohort. Study Design Retrospective case-control study. PPH was classified by an estimated blood loss ≥ 500 mL. Risk factors for PPH were identified using univariable and multivariable logistic regression. We secondarily investigated maternal outcomes and medical and surgical interventions for PPH management. Results The study cohort comprised 159 cases and 318 controls. Compared to a second stage duration

Objectives To determine the trends of cesarean delivery rate among twin pregnancies from 2006 to 2013. Study design This is a population-based, cross-sectional analysis of twin live births from United State birth data files of the National Center for Health Statistics for calendar years 2006 through 2013. We stratified the population based on the gestational age groups, maternal race/ethnicity, advanced maternal age (AMA) which was defined by age more than 35 years and within the standard birth weight groups (group 1: birth weight 500–1499 g, group 2: birth weight 1500–2499 g and group 3: birth weight >2500 g). We also analyzed the effect of different risk factors for cesarean delivery in twins. Results There were 1,079,102 infants born of twin gestations in the U.S. from 2006 to 2013, representing a small but significant increase in the proportion of twin births among all births (3.2% in 2006 versus 3.4% in 2013). The rate of cesarean delivery in twin live births peaked at 75.3% in 2009, and was significantly lower (74.8%) in 2013. The rate of the twin live birth with the breech presentation increased steadily from 26.3% in 2006 to 29.1% in 2013. For the fetus of the twin pregnancy presented as breech, the cesarean delivery rate peaked at 92.2% in 2010, falling slightly but significantly in the ensuing 3 years. The results demonstrated that the decrease in cesarean delivery rate was due to fewer cesareans in non-Hispanic white patients; all other ethnic subgroups showed increasing rates of cesarean delivery throughout the study. Gestational diabetes, gestational hypertension, previous cesarean delivery and breech presentation were all significant risk factors for cesarean delivery during the entire study period. Induction of labor and premature rupture of the membranes were associated with lower rates of cesarean delivery in twins. Conclusion The recent decrease in the cesarean delivery rate in twin gestation appears to be largely attributable to a decline in cesarean among pregnancies complicated by breech presentation in non-Hispanic white women, and may reflect a health care disparity that deserves further research.

When a fetal anomaly is suspected, a multidisciplinary approach to diagnosis, counseling, pregnancy management, surveillance, delivery planning, and neonatal care is critical to creating a comprehensive management plan. This article provides a basic framework for integrating prenatal diagnostic and maternal-fetal care considerations, delivery planning, special resuscitation needs, and immediate and later neonatal care and evaluation into developing a thoughtful management plan for infants with prenatally diagnosed complex anomalies including congenital heart disease, intrathoracic masses, fetal airway obstruction, neural tube defects, abdominal wall defects, and skeletal dysplasia.

First trimester screening for fetal aneuploidy is now the standard of care for pregnant women residing in the United States and other developed nations. Today screening includes both biochemical and ultrasonographic parameters; however, ongoing research and advances in ultrasound and cell-free fetal DNA make this a rapidly evolving and exciting field. For example, it is conceivable that noninvasive fetal genotyping in the first trimester may one day (not so distantly in the future) be incorporated into routine screening paradigms. This review aims to explore advances in first trimester screening and also discusses several potential future directions.

OBJECTIVE:To estimate trends and risk factors for cesarean delivery for twins in the United States.METHODS:This was a cross-sectional study in which we calculated cesarean delivery rates for twins from 1995 to 2008 using National Center for Health Statistics data. We compared cesarean delivery rates

Objective To investigate pregnant women's level of future interest in noninvasive prenatal diagnosis (NIPD) and what factors might affect expected uptake of this testing. Method Written questionnaires were administered to women in their third trimester. Results One hundred fourteen women returned the questionnaire (80.9% response rate). Of these, 71.9% reported interest in NIPD, 22.7% were ambivalent, and 5.4% were uninterested. Safety of the fetus was the single most important factor in 75% of women's decisions. Factors associated with increased interest in NIPD included: older age (p = 0.036), higher education (p = 0.013), Caucasian or Asian ethnicity (p = 0.011), and higher likelihood to terminate an affected pregnancy (p = 0.002). Nearly 20% of women reported that they would do whatever their doctor recommended regarding NIPD, and 94.4% of women wished to meet with a genetic counselor at some point to discuss NIPD. Conclusion The majority of pregnant women report hypothetical interest in NIPD, primarily because of increased safety for the fetus, although a significant minority are uninterested or ambivalent. Discussions with healthcare providers regarding NIPD, and their recommendations, are likely to be an important factor in women's decisions about this testing. As such, adequate discussion of the implications of prenatal diagnostic testing will be critical. Copyright © 2011 John Wiley & Sons, Ltd.

OBJECTIVE: To estimate the effect of preterm premature rupture of membranes (PROM) on neonatal mortality. METHODS: A cross-sectional study using a state perinatal database (California Perinatal Quality Care Collaborative) was performed. Prenatal data, including ruptured membranes, corticosteroid administration, maternal age, maternal race, maternal hypertension, mode of delivery, and prenatal care, were recorded. Mortality rates were compared for neonates born between 24 and 34 weeks of gestation without preterm PROM to those with recent (less than 18 hours before delivery) and prolonged (more than 18 hours before delivery) preterm PROM. Neonatal sepsis rates were also examined. RESULTS: Neonates born between 24 0/7 and 34 0/7 weeks of gestation from 127 California neonatal intensive care units between 2005 and 2007 were included (N=17,501). When analyzed by 2-week gestational age groups, there were no differences in mortality rates between those born with and without membrane rupture before delivery. The presence of prolonged preterm PROM was associated with decreased mortality at 24 to 26 weeks of gestation (18% compared with 31% for recent preterm PROM; odds ratio [OR] 1.79; confidence interval [CI] 1.25–2.56) but increased mortality at 28 to 30 weeks of gestation (4% compared with 3% for recent preterm PROM; OR 0.44; CI 0.22, 0.88) when adjusted for possible confounding factors. Sepsis rates did not differ between those with recent or prolonged preterm PROM at any gestational age. CONCLUSION: The presence of membrane rupture before delivery was not associated with increased neonatal mortality in any gestational age group. The effects of a prolonged latency period were not consistent across gestational ages. LEVEL OF EVIDENCE: III