The Laborist trend: its implications.

PURPOSE: To offer obstetrical practitioners a current perspective about an important contemporary practice model which has implications that may not have been adequately recognized. METHODS: A description of individual past professional experience. RESULTS: A resultant perspective from decades of professional obstetric practice. CONCLUSION: A description of potential clinical impact on patients and practitioners alike.

Does a History-Indicated Cerclage Affect Gestational Age at Delivery in Women with Evidence of Recurrent Cervical Insufficiency?

OBJECTIVE: To determine whether women with recurrent evidence of cervical insufficiency (CI) and with a history-indicated cerclage (HIC) placed at the beginning of the second trimester will deliver later than the index case. STUDY DESIGN: Retrospective case-control study of singleton pregnancy with history-consistent CI. Patients had a cerclage placed between 12 and 16 weeks of gestation. Transvaginal cervical measurement was done between 18 and 24 weeks. Those with a cervical measurement 25 mm were considered to have recurrent CI (Group A). Gestational age at delivery of the index case (Group C) and the cerclage patients (Groups A and B), which are the same patients as Group C, was compared using Student's t test. They have the same genetics and anatomy. RESULTS: A total of 124 women had an HIC. Sixteen (13%) had recurrent CI (Group A). Comparing cases, the proximate average age at delivery was 22 weeks as compared with 33 weeks and 3 days for those with a cerclage (p < 0.001) (Group A vs. B). In those with a cervical length > 25 mm (Group B), 96 (89%) had a term delivery. In the index cases 64% delivered at 22 weeks or less (Group C). CONCLUSION: Cerclage in those patients with recurrent CI has a significantly improved outcome as compared with the index case. This minimizes pregnancy loss.

3-D ultrasound of the fetal ear and fetal autosomal trisomies: a pilot study of a new screening protocol.

OBJECTIVE: We hypothesize that the rotation of the ear in fetuses with common autosomal trisomies will be markedly different from euploid fetuses and amenable to detection by 3-D ultrasound in the render mode. METHODS: Study participants (10 weeks 4 days through 19 weeks 0 days) underwent a 3-D rendering of the fetal face and ear along with other biometric measurements prior to invasive testing. RESULTS: Of the 348 patients who underwent chorionic villi sampling (CVS) (n = 208) or amniocentesis (n = 140), 18 were diagnosed with trisomy 21, 4 with trisomy 18, and 1 with trisomy 13. Mean gestational age was 12 weeks 6 days (range: 10 weeks 6 days to 19 weeks 0 days). Ear angles were obtained in all cases; the time to obtain this angle ranged from 5 to 25 min. Thirty-two fetuses were found to have an abnormal ear angle with 23 of the 32 characterized by one of the aforementioned trisomies. CONCLUSIONS: These findings support the potential of this technique to provide valuable information in the identification of an increased-risk population. Prospective studies are needed to confirm the value of this screening modality as well as to assess its facility and ability to be incorporated into routine obstetrical practice.

Reducing the cesarean delivery rate.

BACKGROUND: The cesarean delivery rate has been rising in recent years, having associated maternal morbidities. Elective induction of labor has also been seen to rise during this same time period. OBJECTIVE: This current study investigated the difference in the cesarean delivery rate between induction of labor and spontaneous labor among nulliparous, term, singleton, and vertex-presenting women. STUDY DESIGN: A retrospective cohort in a single institution over a seven-year period was used for this analysis, observing the difference in cesarean delivery rate at different term gestational ages and neonatal morbidity using the 5-minute Apgar score < 5. RESULTS: A statistically significant difference was found in cesarean delivery rate between those women whose labor was induced and those whose labor began spontaneously, at each term gestational age of labor initiation (P < 0.001). The proportion of indications for induction was described (i.e. elective vs. medically-indicated), and no difference was found for neonatal morbidity between the groups analyzed, using the 5-minute Apgar score as the perinatal outcome measure. CONCLUSION: A comparison was made between spontaneous and induced labor regarding the resultant cesarean delivery rate, and a significant difference was found favoring spontaneous labor. This should be considered when electing to deliver using an induction methodology for nulliparous women, especially when there are no medical indications for it.

Whole Exome Sequencing with Comprehensive Gene Set Analysis Identified a Biparental-Origin Homozygous c.509G>A Mutation in PPIB Gene Clustered in Two Taiwanese Families Exhibiting Fetal Skeletal Dysplasia during Prenatal Ultrasound.

Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.

Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

OBJECTIVE: Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. METHOD: We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. RESULTS: We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. CONCLUSION: These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population.

Noninvasive prenatal diagnosis of fetal aneuploidy by circulating fetal nucleated red blood cells and extravillous trophoblasts using silicon-based nanostructured microfluidics.

BACKGROUND: Noninvasive prenatal testing (NIPT) based on cell-free DNA in maternal circulation has been accepted worldwide by the clinical community since 2011 but limitations, such as maternal malignancy and fetoplacental mosaicism, preclude its full replacement of invasive prenatal diagnosis. We present a novel silicon-based nanostructured microfluidics platform named as "Cell Reveal™" to demonstrate the feasibility of capturing circulating fetal nucleated red blood cells (fnRBC) and extravillous cytotrophoblasts (EVT) for cell-based noninvasive prenatal diagnosis (cbNIPD). METHODS: The "Cell Reveal™" system is a silicon-based, nanostructured microfluidics using immunoaffinity to capture the trophoblasts and the nucleated RBC (nRBC) with specific antibodies. The automated computer analysis software was used to identify the targeted cells through additional immunostaining of the corresponding antigens. The identified cells were retrieved for whole genome amplification for subsequent investigations by micromanipulation in one microchip, and left in situ for subsequent fluorescence in situ hybridization (FISH) in another microchip. When validation, bloods from pregnant women (n = 24) at gestational age 11-13+6 weeks were enrolled. When verification, bloods from pregnant women (n = 5) receiving chorionic villus sampling or amniocentesis at gestation age 11+4-21 weeks with an aneuploid or euploid fetus were enrolled, followed by genetic analyses using FISH, short tandem repeat (STR) analyses, array comparative genomic hybridization, and next generation sequencing, in which the laboratory is blind to the fetal genetic complement. RESULTS: The numbers of captured targeted cells were 1-44 nRBC/2 ml and 1-32 EVT/2 ml in the validation group. The genetic investigations performed in the verification group confirmed the captured cells to be fetal origin. In every 8 ml of the maternal blood being blindly tested, both fnRBC and EVT were always captured. The numbers of captured fetal cells were 14-22 fnRBC/4 ml and 1-44 EVT/4 ml of maternal blood. CONCLUSIONS: This report is one of the first few to verify the capture of fnRBC in addition to EVT. The scalability of our automated system made us one step closer toward the goal of in vitro diagnostics.

Late second trimester assessment of pyelectasis (SERP) to predict pediatric urological outcome is improved by checking additional features.

OBJECTIVE: Counseling for pyelectasis in the late 2nd trimester is usually based only upon assessing the antero-posterior (AP) width of the renal pelvis. We hypothesized that checking additional features would better predict postnatal outcome. STUDY DESIGN: Ultrasound (<24 weeks gestational age (GA)) and newborn outcome data collected prospectively since 1986 were analyzed retrospectively. We determined if outcome predictions in kidneys with a sonographically evident renal pelvis (SERP), which had evaluation of additional features (e.g., renal and bladder lengths, presence of a dilated ureter or dilated calyces) are more accurate than those that did not have these features. RESULTS: There were 286 fetuses studied with pediatric follow-up of an average of 6.5 years. There were 338 exams providing 459 ultrasound images with SERP. Additional features were not assessed in 183 fetuses; however 103 fetuses did have evaluation of additional features. These features were categorized as abnormal (92) or as normal (11). Fetuses with SERP and abnormal additional features required extensive urological care or died 6.1 times more often than fetuses in which additional features were not examined (p < 0.001) and 12.9 times more often when additional features were normal (p < 0.001). CONCLUSION: Fetal kidneys with SERP (<24 weeks GA) and an abnormal additional ultrasound feature had extensive pediatric care significantly more often than when such features were not evaluated or were normal.

The role of cervical cultures to guide perioperative antibiotics in cervical cerclage - a retrospective analysis of 65 consecutive cases.

OBJECTIVE: The objective of this study is to examine results of bacterial cultures of the cervix prior to cerclage placement and how these may be used to guide prophylactic antibiotics. METHODS: All patients undergoing cerclage between 2000 and 2003 in a single, large community hospital were evaluated for indication for cerclage, signs and symptoms on presentation, transvaginal ultrasound cervical length findings, type of cerclage placed, type of anesthesia used, cervical culture taken, tocolytics given, gestational age at delivery, and complications surrounding delivery. RESULTS: Sixty-five cerclages were performed between 2000 and 2003, 13 (20%) prophylactic, 47 (72%) therapeutic, and five (8%) emergent. Cervical cultures were obtained in 85% of patients, of which 40% were negative resulting in no antibiotics given. In the remaining 45%, one or more pathogens were isolated and antibiotics were given according to sensitivities reported. Fifty-five of 65 patients (84%) delivered after 32 weeks gestation and a latency > 60 d was seen in 84%. The incidence of chorioamnionitis and PPROM was low. CONCLUSION: Bacterial cultures of the cervix prior to cerclage show variable colonization and antibiotic sensitivities and, there is no single antibiotic, chosen empirically, that will cover all pathogens.

Validating a rapid, real-time, PCR-based direct mutation detection assay for preimplantation genetic diagnosis.

Although co-amplification of polymorphic microsatellite markers is the current gold standard for preimplantation genetic diagnosis (PGD) of single-gene disorders (SGD), this approach can be hampered by the lack of availability of informative markers. We recently (2011) devised a novel in-house assay for PGD of aromatic L-amino acid decarboxylase deficiency, based on an amplification refractory mutation system and quantitative PCR (ARMS-qPCR). The objective of the present study was to verify ARMS-qPCR in a cohort of 20 PGD cycles with a diverse group of SGDs (15 couples at risk for 10 SGDs). Day-3 cleavage-stage embryos were subjected to biopsy and genotyping, followed by fresh embryo transfer (FET). The diagnostic rate was 82.9%; unaffected live births were achieved in 9 of 20 FET cycles (45%), with only one false negative (among 54 transferred embryos). Overall, the ARMS-qPCR had frequent allele-dropout (ADO), rendering it inappropriate as the sole diagnostic method (despite a favorable live-birth rate). Regardless, it has the potential to complement the current gold-standard methodology, especially when trophectoderm biopsy becomes a preferred option and genotyping needs to be timely enough to enable FET.

Amniotic fluid and serum biomarkers from women with neural tube defect-affected pregnancies: a case study for myelomeningocele and anencephaly: clinical article.

OBJECT: The authors sought to identify novel biomarkers for early detection of neural tube defects (NTDs) in human fetuses. METHODS: Amniotic fluid and serum were drawn from women in the second trimester of pregnancy. The study group included 2 women pregnant with normal fetuses and 4 with fetuses displaying myelomeningocele (n = 1), anencephaly (n = 1), holoprosencephaly (n = 1), or encephalocele (n = 1). Amniotic fluid stem cells (AFSCs) were isolated and cultured. The cells were immunostained for the stem cell markers Oct4, CD133, and Sox2; the epigenetic biomarkers H3K4me2, H3K4me3, H3K27me2, H3K27me3, H3K9Ac, and H3K18Ac; and the histone modifiers KDM6B (a histone H3K27 demethylase) and Gcn5 (a histone acetyltransferase). The levels of 2 markers for neural tube development, bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh), were measured in amniotic fluid and serum using an enzyme-linked immunosorbent assay. RESULTS: The AFSCs from the woman pregnant with a fetus affected by myelomeningocele had higher levels of H3K4me2, H3K4me3, H3K27me2, and H3K27me3 and lower levels of KDM6B than the AFSCs from the women with healthy fetuses. The levels of H3K9ac, H3K18ac, and Gcn5 were also decreased in the woman with the fetus exhibiting myelomeningocele. In AFSCs from the woman carrying an anencephalic fetus, levels of H3K27me3, along with those of H3K9Ac, H3K18ac, and Gcn5, were increased, while that of KDM6B was decreased. Compared with the normal controls, the levels of BMP4 in amniotic fluid and serum from the woman with a fetus with myelomeningocele were increased, whereas levels of Shh were increased in the woman pregnant with a fetus displaying anencephaly. CONCLUSIONS: The levels of epigenetic marks, such as H3K4me, H3K27me3, H3K9Ac, and H3K18A, in cultured AFSCs in combination with levels of key developmental proteins, such as BMP4 and Shh, are potential biomarkers for early detection and identification of NTDs in amniotic fluid and maternal serum.

Genome-wide gene expression analysis implicates the immune response and lymphangiogenesis in the pathogenesis of fetal chylothorax.

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease.

Fusion as the etiology of chimerism in monochorionic dizygotic twins.

In a dizygotic pregnancy within monochorionic placenta, findings consistent with chimerism were detected. Monochorionicity was confirmed by a combination of ultrasound, histological evaluation and DNA technology. Etiologic hypotheses are offered to explain this rare circumstance.