Prior Term Birth Decreases the Risk of Preterm Birth in a Subsequent Twin Gestation.

OBJECTIVE: The aim of the study is to examine the association between the risk of preterm delivery among women with twin pregnancies and their obstetric history. STUDY DESIGN: We designed a retrospective cohort study of live twin births in 2008 in the United States that delivered after 240/7 weeks. Women were categorized into nulliparas, multiparas with prior term delivery, and multiparas with prior preterm delivery. The incidence of preterm birth was compared using Chi-square test and multivariable logistic regression models. RESULTS: A total of 32,895 nulliparous and 64,701 multiparous women with twin pregnancies were included in the study. Of the multiparous women, 2,505 (4%) had a history of a prior preterm delivery. Multiparous women with prior term birth were more likely to deliver at term (: 43%): in the index twin pregnancy than nulliparous women (40%) and multiparous women with a prior preterm birth (21%; p < 0.001). Compared with nulliparous women, prior term birth was protective against preterm delivery (adjusted odds ratio [aOR] = 0.67 [95% confidence interval: 0.60-0.74] for delivery <28 weeks and aOR = 0.79 [0.71-0.77] for delivery <34 weeks). CONCLUSION: Among multiparous women with twins, a prior term delivery appeared to be protective against preterm delivery compared with nulliparous women with twins. KEY POINTS: · Prior term birth is protective against preterm birth in subsequent twin pregnancy.. · A prior term birth confers an OR of 0.66 for delivery prior to 28 weeks in twin pregnancies.. · A prior preterm birth renders a twin pregnancy nearly twice as likely to deliver before 28 weeks..

Disparities in Trial of Labor among Women with Twin Gestations in the United States.

OBJECTIVE: The aim of the study is to examine clinical and demographic factors associated with trial of labor (TOL) among women with twin gestations eligible for a vaginal delivery. STUDY DESIGN: This was a population-based cohort study of women giving birth to twin gestations in the United States (2012-2014). Inclusion criteria for the analysis included live births greater than 23 weeks' gestation and a cephalic presenting twin. Women with prior cesarean delivery were excluded. Women were categorized by whether they underwent a TOL. Clinical and demographic characteristics associated with TOL status were evaluated using multivariable logistic regression analyses. Secondary analyses with stratification by parity and by second twin presentation were performed. RESULTS: Of 90,000 women eligible for inclusion, a minority (39.3%) underwent TOL. Women who had a greater gestational age at delivery were more likely to have a TOL. In contrast, several demographic factors were associated with decreased likelihood of TOL, including maternal age >35 years and identifying as Hispanic or Asian compared with non-Hispanic White. No differences in odds of TOL were observed for women who were identified as non-Hispanic Black versus non-Hispanic White, nor were other demographic factors such as marital status, insurance status, or educational attainment associated with undergoing TOL. Clinical factors associated with decreased odds of TOL included nulliparity, obesity, and hypertensive disorders of pregnancy. Results did not substantively change when stratified by parity or second twin presentation, nor did findings differ in the subgroup who delivered at 32 weeks of gestation or greater. CONCLUSION: In this large population of women with twins who were eligible for a TOL, a minority of individuals attempted a vaginal delivery. Demographic and clinical factors such as older maternal age, Asian or Hispanic racial or ethnic identification, nulliparity, and obesity are associated with decreased odds of undergoing TOL. KEY POINTS: · Understanding disparities in trial of labor among patients with twins is key to promoting equity.. · Older maternal age and identifying as Hispanic or Asian were associated with lower odds of TOL.. · Nulliparity, obesity, and hypertension were associated with decreased odds of TOL..

Perinatal Outcomes of Twin Gestations with and without Gestational Diabetes Mellitus.

OBJECTIVE: Existing data suggest that obstetric outcomes for individuals with twin gestations, who have gestational diabetes mellitus (GDM), may be comparable to those who do not have GDM, yet studies are limited by small sample sizes. The aim of this study was to examine differences in maternal and neonatal outcomes of individuals with twin gestations based on presence of GDM. METHODS: This was a population-based retrospective cohort study of individuals giving birth to twins in the United States between 2012 and 2014. Inclusion criteria were live births (≥24 weeks) and available information on GDM status; individuals with pregestational diabetes were excluded. Participants were categorized as either having had or not had GDM. Multivariable logistic regression was utilized to assess the independent association of GDM with adverse maternal outcomes, whereas generalized estimating equation models were used to estimate associations with neonatal outcomes to account for clustering. RESULTS: Of 173,196 individuals meeting inclusion criteria, 13,194 (7.6%) had GDM. Individuals with GDM were more likely to be older, identify as Hispanic or Asian race and ethnicity, married, college educated, privately insured, and obese than those without GDM. After adjusting for potential confounding variables, those with GDM were more likely to have hypertensive disorders (18.0 vs. 10.2%) and undergo cesarean delivery (51.2 vs. 47.3%). Neonates born to individuals with GDM were more likely to require mechanical ventilation for greater than 6 hours (6.5 vs. 5.6%) and experience neonatal intensive care unit (NICU) admission (41.1 vs. 36.2%), but were less likely to be low birth weight or have small for gestational age status (16.2 vs. 19.5%). Findings were confirmed in a sensitivity analysis of neonates born at 32 weeks of gestation or greater. CONCLUSION: Odds of poor obstetric and neonatal outcomes are increased for individuals with twin gestations complicated by GDM. KEY POINTS: · Individuals with GDM and twin gestation have higher odds of developing hypertensive disorders during pregnancy and of undergoing cesarean delivery.. · Neonates of such pregnancies are less likely to be low birth weight or small for gestational age.. · Neonates of pregnancies complicated by GDM and twin gestation are more likely to require mechanical ventilation and experience NICU admission..

Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing.

Cell-free DNA in human plasma is nonrandomly fragmented and reflects genomewide nucleosomal organization. Previous studies had demonstrated tissue-specific preferred end sites in plasma DNA of pregnant women. In this study, we performed integrative analysis of preferred end sites with the size characteristics of plasma DNA fragments. We mined the preferred end sites in short and long plasma DNA molecules separately and found that these "size-tagged" ends showed improved accuracy in fetal DNA fraction estimation and enhanced noninvasive fetal trisomy 21 testing. Further analysis revealed that the fetal and maternal preferred ends were generated from different locations within the nucleosomal structure. Hence, fetal DNA was frequently cut within the nucleosome core while maternal DNA was mostly cut within the linker region. We further demonstrated that the nucleosome accessibility in placental cells was higher than that for white blood cells, which might explain the difference in the cutting positions and the shortness of fetal DNA in maternal plasma. Interestingly, short and long size-tagged ends were also observable in the plasma of nonpregnant healthy subjects and demonstrated size differences similar to those in the pregnant samples. Because the nonpregnant samples did not contain fetal DNA, the data suggested that the interrelationship of preferred DNA ends, chromatin accessibility, and plasma DNA size profile is likely a general one, extending beyond the context of pregnancy. Plasma DNA fragment end patterns have thus shed light on production mechanisms and show utility in future developments in plasma DNA-based noninvasive molecular diagnostics.

Perioperative prophylactic internal iliac artery balloon occlusion in the prevention of postpartum hemorrhage in placenta previa: a randomized controlled trial.

BACKGROUND: Placenta previa remains one of the major causes of massive postpartum hemorrhage and maternal mortality worldwide. OBJECTIVE: To determine whether internal iliac artery balloon occlusion during cesarean delivery for placenta previa could reduce postpartum hemorrhage and other maternal complications. STUDY DESIGN: This was a prospective randomized controlled trial conducted at a tertiary university obstetric unit in Hong Kong. Pregnant women who were diagnosed to have placenta previa at 34 weeks (defined as lower placenta edge within 2 cm from the internal os) and required cesarean delivery were invited to participate. Eligible pregnant women were randomized into internal iliac artery balloon occlusion (Occlusion) group or standard management (Control) group. Those randomized to the Occlusion group had internal iliac artery balloon catheter placement performed before cesarean delivery and then balloon inflation after delivery of the baby. The primary outcome was the reduction of postpartum hemorrhage in those with internal iliac artery balloon occlusion. Secondary outcome measures included hemoglobin drop after delivery; amount of blood product transfusion; incidence of hysterectomy; maternal complications including renal failure, ischemic liver, disseminated intravascular coagulation, and adult respiratory distress syndrome; length of stay in hospital; admission to intensive care unit; and maternal death. RESULTS: Between May 2016 and September 2018, 40 women were randomized (20 in each group). Demographic and obstetric characteristics were similar between the 2 groups. In the Occlusion group, 3 women did not receive the scheduled procedure, as it was preceded by antepartum hemorrhage that required emergency cesarean delivery, and 1 woman had repeated scan at 36 weeks showing the placental edge was slightly more than 2 cm from the internal os. Intention-to-treat analysis found no significant differences between the Occlusion and the Control groups regarding to the median intraoperative blood loss (1451 [1024-2388] mL vs 1454 [888-2300] mL; P = .945), the median length of surgery (49 [30-62] min vs 37 [30-51] min; P = .204), or the need for blood transfusion during operation (57.9% vs 50.0%; P = .621). None of the patients had rebleeding after operation, complication related to internal iliac artery procedure, or any other maternal complications. Reanalyzing the data using on-treatment approach showed the same results. CONCLUSION: The use of prophylactic internal iliac artery balloon occlusion in placenta previa patients undergoing cesarean delivery did not reduce postpartum hemorrhage or have any effect on maternal or neonatal morbidity.

Monochorionic twins with selective fetal growth restriction: insight from placental whole-transcriptome analysis.

BACKGROUND: The underlying pathomechanism in placenta-related selective fetal growth restriction in monochorionic diamniotic twin pregnancy is not known. OBJECTIVE: This study aimed to investigate any differences in placental transcriptomic profile between the selectively growth-restricted twins and the normally grown cotwins in monochorionic diamniotic twin pregnancies. STUDY DESIGN: This was a prospective study of monochorionic diamniotic twin pregnancies complicated by selective fetal growth restriction. Placental biopsy specimens were obtained from the subjects in the delivery suite. The placental transcriptome of the selectively growth-restricted twin was compared with that of the normally grown cotwin. This study was divided into 2 stages: (1) gene discovery phase in which placental tissues from 5 monochorionic diamniotic twin pregnancies complicated by selective fetal growth restriction plus 2 control twin pregnancies underwent transcriptome profiling, and transcriptome profiling was carried out using whole-genome RNA sequencing; and (2) validation phase in which placental tissues from 13 monochorionic diamniotic twin pregnancies with selective fetal growth restriction underwent RNA and protein validation. RNA and protein expression levels of candidate genes were determined using quantitative real-time polymerase chain reaction and immunohistochemistry staining. RESULTS: A total of 1429 transcripts were differentially expressed in the placentae of selectively growth-restricted twin pairs, where 610 were up-regulated and 819 were down-regulated. Endoplasmic reticulum lectin and mannose 6-phosphate receptor were consistently differentially up-regulated in all placentae of selectively growth-restricted twins. Quantitative real-time polymerase chain reaction and immunohistochemistry staining were used to validate the results (P<.05). CONCLUSION: The expression of endoplasmic reticulum lectin and mannose 6-phosphate receptor, which are important for angiogenesis and fetal growth, was significantly increased in the placentae of selectively growth-restricted twin of a monochorionic twin pair.

The predictive value of cervical shear wave elastography in the outcome of labor induction.

INTRODUCTION: Bishop score, the traditional method to assess cervical condition, is not a promising predictive tool of the outcome of labor induction. As an objective assessment tool, many cervical ultrasound measurements have been proposed to represent the individual components of the Bishop score, but none of them can measure the cervical stiffness. Cervical shear wave elastography is a novel tool to assess the cervical stiffness quantitatively. MATERIAL AND METHODS: A total of 475 women who required labor induction were studied prospectively. Prior to routine digital assessment of the Bishop score, transvaginal sonographic measurement of cervical length, posterior cervical angle, angle of progression and shear wave elastography was performed. Shear wave elastography measurement was made at the inner, middle and outer regions of the cervix to assess homogeneity. Association of labor induction outcomes including the overall cesarean section and subgroups of cesarean section for failure to enter active phase, with cervical sonographic parameters and the Bishop score, were assessed using multivariate regression analyses. The predictive accuracy of the outcomes using models based on ultrasound measurement and the Bishop score was compared using the area under the receiver-operating characteristics curves. RESULTS: Among 475 women, 82 (17.3%) required cesarean section. Shear wave elasticity was significantly higher in the inner cervical region than in other regions, indicating a greater stiffness (P < 0.001). Both inner cervical shear wave elasticity and cervical length were independent predictors of overall cesarean section (respective adjusted odds ratio [95% CI] 1.338 [1.001-1.598] and 1.717 [1.077-1.663]) and cesarean section for failure to enter active phase (respective adjusted odds ratio [95% CI] 1.689 [1.234-2.311] and 2.556 [1.462-4.467]), after adjusting for other covariates. Outcome prediction models using inner cervical shear wave elasticity and cervical length, had increased area under curve compared with models using the Bishop score (0.888 vs 0.819, P = 0.009). CONCLUSIONS: The cervix is not a homogenous structure, with the inner cervix having the highest stiffness, which is an independent predictor of overall cesarean section, and specifically for those indicated because of failure to enter active phase. Models based on shear wave elastography and cervical length had higher predictive accuracy than models based on the Bishop score.

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics.

The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions.

Objective assessment of the fetal facial profile at second and third trimester of pregnancy.

OBJECTIVE: To investigate the intraobserver and interobserver reproducibility of a novel sonographic parameter named facial maxillary angle (FMA) and to establish nomograms of FMA, inferior facial angle (IFA), frontal nasal-mental angle (FNMA), maxilla-nasion-mandible angle (MNMA), and fetal profile line (FPL) in Chinese fetuses. METHODS: In this prospective cross-sectional study, FMA, IFA, FNMA, MNMA, and FPL were measured in 592 normal fetuses between 16 and 36 gestational weeks. FMA was measured twice by the same and another operator with a blinded method on the first 50 cases. The reference interval was defined as ±2SD. The efficacy of five sonographic markers was tested in 10 fetuses with micrognathia retrieved from the database of our unit. RESULTS: The intraclass correlation coefficient (95% CI) of intraobserver and interobserver reproducibility of FMA was 0.937 (0.890-0.964) and 0.891 (0.809-0.938), respectively. FMA, FNMA, and IFA increased slightly from 16 weeks till 28-31 weeks and decreased minimally thereafter. FMA and FNMA made correct diagnosis in all affected fetuses; MNMA and IFA identified nine and eight cases respectively, and FPL only detected five cases. CONCLUSION: A fixed cutoff of 66° for FMA and 136° for FNMA may be adopted as simple screening criteria of micrognathia.

Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends.

Plasma DNA obtained from a pregnant woman was sequenced to a depth of 270× haploid genome coverage. Comparing the maternal plasma DNA sequencing data with the parental genomic DNA data and using a series of bioinformatics filters, fetal de novo mutations were detected at a sensitivity of 85% and a positive predictive value of 74%. These results represent a 169-fold improvement in the positive predictive value over previous attempts. Improvements in the interpretation of the sequence information of every base position in the genome allowed us to interrogate the maternal inheritance of the fetus for 618,271 of 656,676 (94.2%) heterozygous SNPs within the maternal genome. The fetal genotype at each of these sites was deduced individually, unlike previously, where the inheritance was determined for a collection of sites within a haplotype. These results represent a 90-fold enhancement in the resolution in determining the fetus's maternal inheritance. Selected genomic locations were more likely to be found at the ends of plasma DNA molecules. We found that a subset of such preferred ends exhibited selectivity for fetal- or maternal-derived DNA in maternal plasma. The ratio of the number of maternal plasma DNA molecules with fetal preferred ends to those with maternal preferred ends showed a correlation with the fetal DNA fraction. Finally, this second generation approach for noninvasive fetal whole-genome analysis was validated in a pregnancy diagnosed with cardiofaciocutaneous syndrome with maternal plasma DNA sequenced to 195× coverage. The causative de novo BRAF mutation was successfully detected through the maternal plasma DNA analysis.

Association between the Degree of Twin Birthweight Discordance and Perinatal Outcomes.

BACKGROUND: Twin birthweight discordance is associated with adverse outcomes. OBJECTIVE: To determine what degree of twin birthweight discordance is associated with adverse outcomes. STUDY DESIGN: This is a retrospective cohort study of twins with vertex twin A delivered vaginally at 36 to 40 weeks (U.S. Vital Statistics Natality birth certificate registry data 2012-2014). The primary outcome was a composite of neonatal morbidity: 5-minute Apgar < 7, neonatal intensive care unit admission, neonatal mechanical ventilation > 6 hours, neonatal seizure, and/or neonatal transport to a higher level of care. Effect estimates were expressed as incidence rate and adjusted odds ratio (aOR) controlling for confounding using multivariate clustered analysis for between-pair effects, and multilevel random effect generalized estimating equation regressions to account for within-pair effects. We adjusted for sex discordance, breech delivery of the second twin, maternal race/ethnicity, nulliparity, age, marital status, obesity, and socioeconomic status. RESULTS: In comparison to birthweight discordance of ≤20%, aORs with 95% confidence intervals (CIs) by weight discordance of the primary outcome among 27,276 twin deliveries were as follows: 20.01 to 25% (aOR: 1.46 [95% CI: 1.29-1.65]); 25.01 to 30% (aOR: 1.96 [95% CI: 1.68-2.29]); and 30.01 to 60% (aOR: 2.97 [95% CI: 2.52-3.50]). CONCLUSION: Twin birthweight discordance >20% was associated with increased odds of adverse neonatal outcome.

Gestational Weight Gain during Pregnancy as an Important Factor Influencing a Successful Trial of Labor following Two Previous Cesareans.

OBJECTIVE: We sought to identify factors associated with a successful trial of labor (TOL) following two cesarean deliveries (CDs) in a contemporary North American cohort. STUDY DESIGN: This is a retrospective cohort study of term, nonanomalous, singleton, vertex pregnancies attempting a vaginal birth after cesarean (VBAC) following a history of two previous CDs in the United States from 2012 to 2014. Maternal and intrapartum factors were analyzed using chi-square tests and multivariable logistic regression. RESULTS: A total of 22,762 women met the inclusion criteria and underwent TOL. Of these, 12,192 (53.6%) had a VBAC. Using multivariate logistic regression, previous vaginal delivery and delivery at 40 to 41 weeks' gestation were associated with VBAC; maternal age, education, Medicaid insurance, non-Caucasian race/ethnicity, weight (overweight or obese), and gestational weight gain above the Institute of Medicine guidelines (adjusted odds ratio: 0.88; 95% confidence interval: 0.81-0.95) were associated with CD. Induction of labor did not affect the VBAC rate. CONCLUSION: For those desiring a TOL after two previous CDs, prospective studies are needed to assess interventions that limit gestational weight gain as well as the safety and optimal timing of an induction of labor. The decision to attempt a TOL should be guided by counseling regarding the risks, benefits, and chances of a successful TOL.

Planned Out-of-Hospital Birth and Birth Outcomes.

BACKGROUND: The frequency of planned out-of-hospital birth in the United States has increased in recent years. The value of studies assessing the perinatal risks of planned out-of-hospital birth versus hospital birth has been limited by cases in which transfer to a hospital is required and a birth that was initially planned as an out-of-hospital birth is misclassified as a hospital birth. METHODS: We performed a population-based, retrospective cohort study of all births that occurred in Oregon during 2012 and 2013 using data from newly revised Oregon birth certificates that allowed for the disaggregation of hospital births into the categories of planned in-hospital births and planned out-of-hospital births that took place in the hospital after a woman's intrapartum transfer to the hospital. We assessed perinatal morbidity and mortality, maternal morbidity, and obstetrical procedures according to the planned birth setting (out of hospital vs. hospital). RESULTS: Planned out-of-hospital birth was associated with a higher rate of perinatal death than was planned in-hospital birth (3.9 vs. 1.8 deaths per 1000 deliveries, P=0.003; odds ratio after adjustment for maternal characteristics and medical conditions, 2.43; 95% confidence interval [CI], 1.37 to 4.30; adjusted risk difference, 1.52 deaths per 1000 births; 95% CI, 0.51 to 2.54). The odds for neonatal seizure were higher and the odds for admission to a neonatal intensive care unit lower with planned out-of-hospital births than with planned in-hospital birth. Planned out-of-hospital birth was also strongly associated with unassisted vaginal delivery (93.8%, vs. 71.9% with planned in-hospital births; P<0.001) and with decreased odds for obstetrical procedures. CONCLUSIONS: Perinatal mortality was higher with planned out-of-hospital birth than with planned in-hospital birth, but the absolute risk of death was low in both settings. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

Pitfalls in assessing chorioamnionicity: novel observations and literature review.

Accurate diagnosis of chorioamnionicity in multiple pregnancies is the key to appropriate clinical management of multiple gestation. Although prenatal ultrasound assessment of chorioamnionicity is well established and highly accurate if performed in early pregnancy, exceptions and artifacts arise from anatomic variations in multiple pregnancies and unusual sonographic features do exist. We have summarized our own experiences and reports from the literature on these pitfalls as follows: (1) discordant fetal sex in monochorionic pregnancies due to sex chromosome abnormalities, genital malformation in 1 fetus, or dizygotic twins forming a monochorionic placenta; (2) separate placental masses in monochorionic pregnancies due to bipartite placenta; (3) false-negative and false-positive λ sign can arise for various reasons, and in partial monochorionic/dichorionic placentas both T and λ sign may co-exist; (4) intrauterine synechia appearing as a thick and echogenic intrauterine septum may lead to erroneous diagnosis of dichorionic twins; and (5) errors in ascertaining amnionicity by the visualization of thin intertwin amniotic membranes and the number of yolk sacs. The ultrasound techniques to reduce inaccuracy in prenatal determination of chorioamnionicity and the use of single nucleotide polymorphisms based on noninvasive prenatal test to determine zygosity are also reviewed.

Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments.

Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.

Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases.

BACKGROUND: Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing. METHODS: We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus. RESULTS: Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified. CONCLUSIONS: High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutation-specific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease.

Association between gestational weight gain and perinatal outcomes in women with chronic hypertension.

BACKGROUND: Gestational weight gain above or below the 2009 National Academy of Medicine guidelines has been associated with adverse maternal and neonatal outcomes. Although it has been well established that excess gestational weight gain is associated with the development of gestational hypertension and preeclampsia, the relationship between gestational weight gain and adverse perinatal outcomes among women with pregestational (chronic) hypertension is less clear. OBJECTIVE: The objective of this study was to examine the relationship between gestational weight gain above and below National Academy of Medicine guidelines and perinatal outcomes in a large, population-based cohort of women with chronic hypertension. STUDY DESIGN: This is a population-based retrospective cohort study of women with chronic hypertension who had term, singleton, vertex births in the United States from 2012 through 2014. Prepregnancy body mass index was calculated using self-reported prepregnancy weight and height. Women were categorized into 4 groups based on gestational weight gain and prepregnancy body mass index: (1) weight gain less than, (2) weight gain within, (3) weight gain 1-19 lb in excess of, and (4) weight gain ≥20 lb in excess of the National Academy of Medicine guidelines. The χ2 tests and multivariable logistic regression analysis were used for statistical comparisons. Stratified analyses by body mass index category were additionally performed. RESULTS: In this large birth cohort, 101,259 women met criteria for inclusion. Compared to hypertensive women who had gestational weight gain within guidelines, hypertensive women with weight gain ≥20 lb over National Academy of Medicine guidelines were more likely to have eclampsia (adjusted odds ratio, 1.93; 95% confidence interval, 1.54-2.42) and cesarean delivery (adjusted odds ratio, 1.60; 95% confidence interval, 1.50-1.70). Excess weight gain ≥20 lb over National Academy of Medicine guidelines was also associated with increased odds of 5-minute Apgar <7 (adjusted odds ratio, 1.29; 95% confidence interval, 1.13-1.47), neonatal intensive care unit admission (adjusted odds ratio, 1.23; 95% confidence interval, 1.14-1.33), and large-for-gestational-age neonates (adjusted odds ratio, 2.41; 95% confidence interval, 2.27-2.56) as well as decreased odds of small-for-gestational-age status (adjusted odds ratio, 0.52; 95% confidence interval, 0.46-0.58). Weight gain 1-19 lb over guidelines was associated with similar fetal growth outcomes although with a smaller effect size. In contrast, weight gain less than National Academy of Medicine guidelines was not associated with adverse maternal outcomes but was associated with increased odds of small for gestational age (adjusted odds ratio, 1.31; 95% confidence interval, 1.21-1.52) and decreased odds of large-for-gestational-age status (adjusted odds ratio, 0.86; 95% confidence interval, 0.81-0.92). Analysis of maternal and neonatal outcomes stratified by body mass index demonstrated similar findings. CONCLUSION: Women with chronic hypertension who gain less weight than National Academy of Medicine guidelines experience increased odds of small-for-gestational-age neonates, whereas excess weight gain ≥20 lb over National Academy of Medicine guidelines is associated with cesarean delivery, eclampsia, 5-minute Apgar <7, neonatal intensive care unit admission, and large-for-gestational-age neonates.

Duration of Second Stage of Labour at Term and Pushing Time: Risk Factors for Postpartum Haemorrhage.

BACKGROUND: Prolonged labour is associated with increased risk of postpartum haemorrhage (PPH), but the role of active pushing time and the relation with management during labour remains poorly understood. METHODS: A population-based cohort study from electronic medical record data in the Stockholm-Gotland Region, Sweden. We included 57 267 primiparous women with singleton, term gestation, livebirths delivered vaginally in cephalic presentation in 2008-14. We performed multivariable Poisson regression to estimate the association between length of second stage, pushing time, and PPH (estimated blood loss >500 mL during delivery), adjusting for maternal, delivery, and fetal characteristics as potential confounders. RESULTS: The incidence of PPH was 28.9%. The risk of PPH increased with each passing hour of second stage: compared with a second stage <1 h, the adjusted relative risk (RR) for PPH were for 1 to <2 h 1.10 (95% confidence interval (CI) 1.07, 1.14); for 2 to <3 h 1.15 (95% CI 1.10, 1.20); for 3 to <4 h 1.28 (95% CI 1.22, 1.33); and for ≥4 h 1.40 (95% CI 1.33, 1.46). PPH also increased with pushing time exceeding 30 min. Compared to pushing time between 15 and 29 min, the RR for PPH were for <15 min 0.98 (95% CI 0.94, 1.03); for 30-44 min 1.08 (95% CI 1.04, 1.12); for 45-59 min 1.11 (95% CI 1.06, 1.16); and for ≥60 min 1.20 (95% CI 1.15, 1.25). CONCLUSIONS: Increased length of second stage and pushing time during labour are both associated with increased risk of PPH.

Prenatal Diagnosis of a Retroesophageal Left Brachiocephalic Vein: Two Case Reports.

A retroesophageal left brachiocephalic vein is an extremely rare anomaly and has only been reported in 6 postnatal cases. Two prenatally diagnosed cases are reported. On the 3-vessel view, the vein appears as an aberrant vessel transversely coursing behind the aorta and trachea, which subsequently drains into the superior vena cava, giving rise to a U-shaped configuration. On color Doppler sonography, the U sign is bicolored. This anomaly should prompt the sonographer to carefully assess for other congenital heart defects, suggest consideration for genetic testing, and alert the cardiologist because it could affect central line procedures and cardiac interventions after delivery.

Procedure-Related Fetal Loss following Chorionic Villus Sampling after First-Trimester Aneuploidy Screening.

OBJECTIVE: The aim was to determine the institutional procedure-related fetal loss rate after chorionic villus sampling (CVS) and the factors which may identify pregnancies at increased risk of having a procedure-related loss. MATERIALS AND METHODS: Pregnancy outcomes were retrieved of all women having a singleton pregnancy and undergoing a CVS procedure between 2004 and 2013 at a university hospital in Hong Kong. The incidence of procedure-related fetal loss due to unintended miscarriages adjusted for the background loss incidence of miscarriages was determined. Multivariate regression was performed to examine the factors contributing to an unintended fetal loss and miscarriage. RESULTS: CVS was performed on 1,906 fetuses. The procedure-related fetal loss rate was 0.17% (95% CI -0.2 to 0.7). After multivariate analysis, a decreased plasma protein-A (PAPP-A) multiple of the median (OR 0.27; 95% CI 0.08-0.98, p = 0.046) was significantly associated with miscarriage in women who did not undergo a CVS. Patient-specific prediction of spontaneous abortion in women who did not undergo CVS was not statistically significant (AUC 0.56; 95% CI 0.49-0.6, p = 0.14). CONCLUSIONS: The CVS-related fetal loss rate adjusted for background loss was 0.17%. Pregnancies with reduced PAPP-A carry an increased risk of miscarriage irrespective of whether they had undergone an invasive procedure.