Higher risk of hemorrhage and maternal morbidity in vaginal birth after second stage of labor C-section.

PURPOSE: This study evaluated the association between timing and indication for previous cesarean section (C-section) and its association with postpartum risks for adverse maternal outcomes, primarily postpartum hemorrhage (PPH) in vaginal birth after cesarean (VBAC). METHODS: This retrospective case-control study examined women following term vaginal delivery in a university-affiliated medical center between 2008 and 2018. Postpartum complications were compared between women who had their first VBAC and a control group comprised of women who had vaginal delivery without prior C-section. Additional analysis was performed to evaluate the association between the timing of previous C-section and the severity of postpartum adverse outcomes. RESULTS: Of the women meeting the inclusion criteria (n = 2879), 1,455 had VBAC and 1,424 were in the control group. Overall, significant postpartum complications, primarily PPH, were observed in the VBAC group compared to controls. Women who underwent C-section during second-stage of labor experienced higher PPH rates and increased drop in hemoglobin levels compared to women who underwent C-section during the first stage of labor or an elective C-Sect. (4.3 ± 0.9 g/dL vs. 2.8 ± 1.1 g/dL vs. 2.4 ± 0.8, p = 0.033). Concomitant increased need for blood transfusion (8.1% vs. 3.5% vs. 2.9%, respectively, p < 0.0001) and uterine atony (12.6% vs. 6.2% vs. 4.4%, respectively, p = 0.009) were also observed. No significant differences were demonstrated in other postpartum adverse effects evaluated. CONCLUSION: VBAC is associated with higher rates of postpartum complications, primarily PPH. The risk is significantly increased in VBAC following a second stage cesarean section. This data should be taken into consideration in the management of laboring women after C-section.

The impact of preimplantation genetic testing on prenatal diagnostic procedures.

OBJECTIVE: In recent years, cell-free DNA screening has significantly reduced the number of invasive prenatal diagnostic testing in pregnancy. Preimplantation genetic testing for aneuploidies (PGT-A) is a commonly performed screening test in in vitro fertilization (IVF) pregnancies. Therefore, we aimed to determine the impact of PGT-A on subsequent utilization of prenatal diagnostic testing in IVF pregnancies. METHODS: Retrospective cohort of singleton and twin IVF pregnancies at a single center from January 2014 to December 2017. The rate of invasive diagnostic genetic testing (chorionic villus sampling (CVS) and/or amniocentesis) was compared between patients with pregnancies achieved after transfer of a euploid embryo by PGT-A (n = 71) and those with pregnancies achieved after transfer of an untested embryo (n = 38). Wilcoxon rank sum and Fisher's exact tests were used for statistical analysis. RESULTS: There was no statistically significant difference in the number of prenatal diagnostic procedures (25.4% PGT-A euploid embryo versus 31.6% untested embryo, p = .51 and p = .32 for one-sided and two-sided analyses, respectively) between the two groups. Maternal age, nuchal translucency measurements and the rate of abnormal sonographic findings were similar between the two groups. Patients without PGT-A pregnancies had a higher BMI (mean 29.6, p = .01) and were ethnically different (p = .013) compared to those with PGT-A. CONCLUSION: The implementation of PGT-A in IVF patients did not reduce the number of invasive diagnostic tests performed at our institution.

Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Birth.

Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13-16 of gestation. At days 15 and 16, lipopolysaccharide (30 µg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/µl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02 u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02 u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01 u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04 u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001 pmol/µl; p < 0.01) to levels similar to controls. A similar pattern was demonstrated in the placenta. Maternal nVP for PTB may protect the fetal brain from inflammation-induced brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta.

The risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤25 mm) at 23-28 weeks' gestation.

BACKGROUND: Asymptomatic short cervical length is an independent risk factor for spontaneous preterm birth. However, most studies have focused on the associated risk of a short cervical length when encountered between 16 and 23 weeks' gestation. The relationship between cervical length and risk of spontaneous preterm birth after 23 weeks is not well known. OBJECTIVE: To evaluate the risk of spontaneous preterm birth in asymptomatic women with a short cervix (≤25 mm) at 23-28 weeks' gestation. MATERIALS AND METHODS: A retrospective cohort study of women with asymptomatic short cervix (cervical length ≤25 mm) at extreme prematurity, defined as 23-28 weeks' gestation, was performed at a single center from January 2015 to March 2018. Women with symptoms of preterm labor, multiple gestations, fetal or uterine anomalies, cervical cerclage, or those with incomplete data were excluded from the study. Demographic information as well as data on risk factors for spontaneous preterm birth were collected. Patients were divided into 4 groups based on the cervical length measurement (≤10 mm, 11-15 mm, 16-20 mm, and 21-25 mm). The primary outcome was time interval from enrollment to delivery. Secondary outcomes included delivery within 1 and 2 weeks of enrollment, gestational age at delivery, and delivery prior to 32, 34, and 37 weeks, respectively. Continuous variables were compared using Kruskal-Wallis test, whereas categorical variables were compared using the χ2 or Fisher exact test as appropriate. The Wilcoxon test for difference in survival time was used to compare gestational age at delivery among the 4 cervical length groups, with data stratified based on gestational age at enrollment. RESULTS: Of the 126 pregnancies that met inclusion criteria, 22 (17.4%) had a cervical length of ≤10 mm, 23 (18.3%) had a cervical length of 11-15 mm, 37 (29.4%) had a cervical length of 16-20 mm, and 44 (34.9%) had a cervical length of 21-25 mm. Baseline characteristics were similar among all 4 groups. The shorter cervical length group was associated with a shorter time interval from enrollment to delivery (cervical length ≤10 mm, 10 weeks; cervical length 11-15 mm, 12.7 weeks; cervical length of 16-20 mm, 13 weeks; cervical length of 21-25 mm, 13.2 weeks; P = .006). Regardless of the cervical length measurement, delivery within 2 weeks was extremely uncommon (1 patient; 0.8%). The prevalence of spontaneous preterm birth at <32 weeks or <34 weeks was higher in women with a cervical length of ≤10 mm compared to those with a longer cervical length (P < .001). CONCLUSIONS: The risk of spontaneous preterm birth in asymptomatic women with a sonographic short cervix increases as cervical length decreases. The risk is substantially higher in women with a cervical length of ≤10 mm. Women with a cervical length of ≤10 mm also had the shortest time interval to delivery. Nevertheless, delivery within 1 or 2 weeks is highly unlikely, regardless of the cervical length at the time of enrollment. Therefore, based on our data, we suggest that management decisions such as timing of administration of antenatal corticosteroids in asymptomatic patients with a cervical length of ≤25 mm at 23-28 weeks' gestation may be delayed until additional indications are present.

Microarray analysis: First-trimester maternal serum free ß-hCG and the risk of significant copy number variants.

OBJECTIVE: To determine whether abnormal levels of first-trimester maternal serum free ß-hCG and PAPP-A are associated with significant copy number variants (CNVs) on chromosomal microarray analysis (CMA). METHODS: Retrospective cohort of singleton prenatal CMA studies (n = 2880). Cases with an abnormal karyotype, benign familial or de novo variants, and absence of heterozygosity were excluded. The prevalence of abnormal serum analytes was compared between patients with significant CNVs (n = 56) and those with normal CMA (n = 884). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using Fisher's exact test. Mantel-Haenszel method was utilized to adjust ORs for prenatal diagnostic procedure type and indications for testing. Statistical significance was determined as P value < 0.05. RESULTS: Abnormally low serum free ß-hCG (≤0.45 MoM) was associated with an increased risk of significant CNVs (OR 3.53, 95% CI, 1.25-8.66, P < 0.01). This association remained significant after adjusting for abnormal nuchal translucency and advanced maternal age (AMA) (adjusted OR 3.04, 95% CI, 1.05-7.48, P < 0.05) or procedure type and AMA (adjusted OR 3.21, 95% CI 1.13-8.16, P < 0.05). The associations of abnormally high serum free ß-hCG, low PAPP-A, and high PAPP-A with significant CNVs were not statistically significant. CONCLUSION: Low first-trimester serum ß-hCG is associated with an increased risk of significant CNVs on CMA.

The Effects of Magnesium Sulfate on the Inflammatory Response of Placentas Perfused With Lipopolysaccharide: Using the Ex Vivo Dual-Perfused Human Single-Cotyledon Model.

OBJECTIVES: Multiple mechanisms have been proposed for the neuroprotective effects of magnesium sulfate (MgSO4). We aimed to examine the effects of lipopolysaccharide (LPS) and MgSO4 on the placental expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), interleukin (IL) 6, adrenocorticotropic hormone (ACTH), and nitric oxide synthase (NOS); all known to participate in the inflammatory cascade. METHODS: Placentas were obtained and selected cotyledons cannulated and dually perfused ex vivo. Placentas were perfused with 4 perfusion protocols: culture medium (M-199; controls), LPS (1 µg/mL), MgSO4 (6 g/dL), and LPS + MgSO4. Each perfusion experiment continued for 3 hours. Sixteen perfusion experiments were analyzed, 4 separate placentas were studied for each protocol. The protein levels in the perfused cotyledons were studied by Western blot analysis and compared between the groups. Interleukin 6 levels were studied in the maternal and fetal perfusate. RESULTS: The expression of NF-κB p65, IL-6, ACTH, and NOS proteins levels were significantly increased in placentas perfused with LPS as compared to placentas perfused with M-199, MgSO4 ( P < .01 for all). Placentas perfused with LPS+ MgSO4 had similar proteins levels as in the controls and MgSO4 groups. Lipopolysaccharide significantly increased IL-6 levels in maternal perfusate. CONCLUSIONS: In the human placenta, MgSO4 blocks the increase in the proteins levels of NF-κB, IL-6, ACTH, and NOS in response to inflammatory stimuli. Magnesium sulfate attenuates excessive placental inflammatory response. The decrease in placental ACTH levels following perfusion with MgSO4 may point to an additional non-anti-inflammatory mechanism of MgSO4.

Major underestimation and overestimation of visual blood loss during cesarean deliveries: can they be predicted?

PURPOSE: The surgeons' visual estimation is the most widely used method for estimating blood loss (BL) while performing cesarean deliveries (CDs). Major BL underestimation may adversely influence obstetric decision making, and result in delaying interventions. Major BL overestimation may result in unnecessary costly interventions. Therefore, we aimed to identify independent predictors for major BL underestimation and overestimation during CDs. METHODS: All CDs performed between 11/2008 and 6/2016, in a university-affiliated hospital, were reviewed for demographic and surgical data, including the surgeons' reported estimated BL (EBL). Calculated BL (CBL) was calculated by multiplying the calculated maternal blood volume by the percent of hematocrit decrease. Multivariate logistic regressions were performed to identify independent risk factors for major BL underestimation (CBL-EBL ≥ 400 ml) and overestimation (EBL-CBL ≥ 400 ml). RESULTS: During the study period, 3655 CDs were analyzed, of which 420 met the criterion for major BL underestimation and 1214 for major BL overestimation. Urgent surgery (aOR = 2.83; 95% CI 2.06-3.89), general anesthesia (aOR = 2.39; 95% CI 1.71-3.33), and higher surgeon experience (aOR = 1.03; 95% CI 1.01-1.06) were found to be independent risk factors for major BL underestimation, while any previous CD (aOR = 0.47; 95% CI 0.33-0.67) decreased the risk of underestimation. Any previous CD (aOR = 1.29; 95% CI 1.05-1.58) and intra-abdominal adhesions (aOR = 1.37; 95% CI 1.11-1.70) were found to be independent risk factors for major BL overestimation, while urgent CD (aOR = 0.50; 95% CI 0.41-0.60) decreased the risk of overestimation. CONCLUSION: Various factors can predict major underestimation and overestimation of BL during CDs. Recognizing these factors can assist in the interpretation of visual EBL and improve obstetric decision making.

Nucleated Red Blood Cells as a Marker of Acute and Chronic Fetal Hypoxia in a Rat Model.

OBJECTIVE: To examine the relationship between duration of fetal hypoxia, nucleated red blood cell (NRBC) count, and fetal growth. METHODS: Pregnant rats were exposed to a severe hypoxia (9.5%-10% O2) for varying time intervals (2, 6, 12, 24, 48, and 120 hours; n=4 for each time interval) immediately prior to delivery at term. Normoxic controls were exposed to room air (21% O2) and matched for all other study variables (n=4 rats for each time interval). Pups were delivered via hysterotomy while maintaining exposure gas concentrations. Blood gas analysis and NRBC counts were performed, and fetal body and liver weights were recorded. Student's t test and simple regression were used for statistical analysis. RESULTS: As the duration of hypoxia increased, fetal weight, liver weight, blood bicarbonate, and base excess levels decreased significantly; concomitantly, NRBC counts increased. This increase in NRBCs became statistically significant after 24 hours of exposure. After 48 hours of hypoxia there was a 2.5-fold rise in NRBC count, and after 120 hours of hypoxia there was a 4.5-fold rise in NRBC count over control levels. After 12 or more hours of hypoxia, fetal body weights were significantly reduced; 120 hours of hypoxia resulted in a 35% reduction in fetal body weight, a 34% reduction in fetal liver weight, and 356% increase in NRBC count. CONCLUSION: In a pregnant rat model, chronic maternal hypoxia (≥24 hours) results in a significant increase in fetal NRBC counts as well as reduced fetal body weight and organ growth.

Universal Prenatal Chromosomal Microarray Analysis: Additive Value and Clinical Dilemmas in Fetuses with a Normal Karyotype.

Objective To assess the additive value of prenatal chromosomal microarray analysis (CMA) for all indications and the likelihood of detecting pathologic copy number variations (CNVs) based on specific indications. Methods A retrospective analysis was performed on amniocentesis and chorionic villi sampling results obtained between 2010 and 2014 in a single institution. A total of 3,314 consecutive patients undergoing invasive genetic testing for different indications were offered CMA in addition to standard karyotype. The prevalence of pathologic CNVs was compared between patients with low-risk indications and those with high-risk indications. Likewise, the prevalence of pathologic CNVs among patients with different sonographic abnormalities was calculated and compared with the low-risk group. Chi-square and Fisher exact tests were used for statistical analysis. Results The prevalence of pathologic CNVs was significantly higher in patients with high-risk indications and specifically those with sonographic abnormalities, compared with the low-risk group (2.8 and 5.9% vs. 0.4%, respectively; all p < 0.05). Conclusion Prenatal CMA detected clinically relevant CNVs in fetuses with a normal karyotype. Major structural malformations and nuchal translucency (NT) ≥ 3.0 mm are associated with the highest risk for a CMA abnormality. Nevertheless, the prevalence of pathologic CNVs in the low-risk population was high enough (1:250) to consider genetic counseling in this group.

Obstetric and neonatal outcome following minor trauma in pregnancy. Is hospitalization warranted?

OBJECTIVE: To evaluate if hospitalization of pregnant women, involved in minor trauma, for 24h of surveillance, is warranted. STUDY DESIGN: The medical files of pregnant women involved in minor trauma, during 2009-2014, at 22-42 gestational weeks, were reviewed. Minor trauma was defined as an injury severity score <3, no immediate complains, normal ultrasound evaluation, reactive non-stress test, and no regular contractions. Patients were divided into those who, according to our departmental protocol, were hospitalized for 24h observation (hospitalized group), and those who refused to be hospitalized, (non-hospitalized group). Pregnancy, delivery and neonatal outcomes were compared between the groups. RESULTS: Included in the study were 946 minor trauma patients that met the inclusion criteria. Gestational age (GA) at the trauma event was lower in the non-hospitalized group (n=331) compared to the hospitalized group (n=615), 29.1 vs. 30.8 weeks, p<0.001, respectively. There were no between-groups differences in the rate of preterm birth, vaginal bleeding, GA at delivery, or cesarean delivery. There were no cases of placental abruption or intrauterine fetal death in both groups. Neonatal outcome did not differ between the groups. CONCLUSION: Minor trauma during pregnancy, with normal initial assessment, is not associated with adverse pregnancy outcomes. Therefore, routine hospitalization is probably not warranted.

Pregnancy outcome and placental pathology differences in term gestational diabetes with and without hypertensive disorders.

OBJECTIVE: To compare pregnancy outcome and placental pathology in pregnancies complicated by gestational diabetes mellitus (GDM A1 and A2), with and without hypertensive disorders. METHODS: Pregnancy outcome and placental pathology from term deliveries of women complicated with GDM with (GDM + H) and without (GDM - H) hypertensive disorders were compared. Results of the GDM + H group were compared also with the non-diabetic patients but with hypertensive disorders (non-GDM + H). Composite neonatal outcome was defined as one or more of early complications: respiratory distress or need of ventilation support, sepsis, phototherapy, transfusion, seizure, hypoxic-ischemic encephalopathy. Placental lesions were categorized to lesions related to maternal and fetal vascular supply abnormalities, and maternal and fetal inflammatory responses. RESULTS: Of the 192 women with GDM, the GDM + H group (n = 41) were more obese, p < 0.001, with higher rate of placental maternal and fetal vascular supply lesions, p = 0.008, p = 0.03, respectively, but similar neonatal outcome, compared to the GDM - H (n = 151) group. Compared to the non-GDM + H group (n = 41), the GDM + H group had higher birth weights, similar neonatal outcome and similar rate of placental vascular lesions. CONCLUSIONS: Higher rate of placental maternal and fetal vascular supply lesions express underlying placental pathology in women with diabetes and hypertensive disorders, similar to women without DM and with hypertensive complications.

Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring.

OBJECTIVE: Maternal chorioamnionitis is associated with newborn neurologic injury. Recent evidence suggests that maternal administration of magnesium sulphate (MG) may protect fetuses from white matter injury. Previously we demonstrated evidence by magnetic resonance imaging that MG may prevent maternal inflammation-induced gray matter injury of offspring. Thus, we sought to determine the potential of maternal inflammation to induce fetal neurological/behavioral deficits and assess whether maternal MG attenuates these effects. STUDY DESIGN: Pregnant rats at day 18 received injections of intraperitoneal lipopolysaccharide (LPS) or saline. Dams were treated with subcutaneous saline/MG (270 mg/kg followed by 27 mg/kg every 20 minutes) for 2 hours before and following LPS/saline injections. Pups were delivered spontaneously. At 1 and 3 months of age, 11-12 offspring of each group (saline, LPS, MG, LPS-MG) underwent a 2-way shuttle box avoidance testing. The shuttle box is divided in half and the animal moves between compartments to avoid an electric shock in response to an auditory stimulus. RESULTS: Control offspring demonstrated significantly improved learning and memory abilities from age 1 to 3 months. At 1 month, LPS-treated dams' offspring were similar to controls with no improvement in learning abilities at 3 months. MG treatment of LPS dams significantly improved offspring learning at 3 months, to equal or better than that of controls. CONCLUSION: LPS-stimulated inflammation during pregnancy impairs offspring learning ability and memory, which is ameliorated by maternal MG treatment. These results suggest that maternal MG therapy may prevent white and gray matter injuries associated with maternal infection/inflammation.

The Effect of Maternal Obesity on Pregnancy Outcome in Correlation With Placental Pathology.

OBJECTIVES: To investigate the effect of maternal obesity on pregnancy outcome and placental histopathology. STUDY DESIGN: Pregnancy outcome and placental histology from term pregnancies were reviewed. Women were divided according to their prepregnancy body mass index (BMI, kg/m(2)) as normal weight (18-24.9) and obese (≥ 30). Pregnancy outcome and placental histology were compared between obese and normal weight women with complicated pregnancies, and with uncomplicated pregnancies, matched by mode of delivery. Placental lesions were classified as lesions of maternal or fetal vascular supply and maternal (MIR) and fetal (FIR) inflammatory responses. RESULTS: Of the 1047 complicated pregnancies analyzed, 615 were with normal weight (BMI 21.7 ± 1.8) and 221 were obese (BMI 35.2 ± 4.3). Obesity was associated with higher rates of diabetes and hypertensive disorders (P = .001 for both), birth weight >90th, P < .001, and cesarean delivery, P < .001. Placental weight was higher in obese than in normal weight women, P < .001. No difference was observed in the rate of placental lesions related to maternal or fetal vascular supply and MIR or FIR between the groups. However, higher rate of maternal placental vascular lesions (46.8% vs 28.2%, P = .012) was observed in uncomplicated obese women (n = 62) as compared with healthy normal weight (n = 124) uncomplicated controls. CONCLUSION: Pregnancy outcome is worse without different placental component in obese versus normal weight women, with complicated pregnancies. In uncomplicated pregnancies, more maternal placental vascular supply lesions exist in obese versus normal weight women, suggesting background placental compromise.

A Preliminary Study of Three-dimensional Sonographic Measurements of the Fetus.

OBJECTIVES: This study was aimed at establishing an ideal method for performing three-dimensional measurements of the fetus in order to improve the estimation of fetal weight. METHODS: The study consisted of two phases. Phase I was a prospective cross-sectional study performed between 28 and 40 weeks' gestation. The study population (n=110) comprised low-risk singleton pregnancies who underwent a routine third-trimester sonographic estimation of fetal weight. The purpose of this phase was to establish normal values for the fetal abdominal and head volumes throughout the third trimester. Phase II was a prospective study that included patients admitted for an elective cesarean section or for induction of labor between 38 and 41 weeks' gestation (n=91). This phase of the study compared the actual birth weight to two- (2D) and three-dimensional (3D) measurements of the fetus. Conventional 2D ultrasound fetal biometry was performed measuring the biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur diaphysis length (FL). Volume estimates were computed utilizing Virtual Organ Computer-aided AnaLysis (VOCAL), and the correlation between measured volumes and actual neonatal weight was calculated. RESULTS: Overall, this longitudinal study consisted of 110 patients between 28 and 41 weeks' gestation. Normal values were computed for the fetal abdomen and head volume throughout the third trimester. Ultrasound examination was performed within three days prior to delivery on 91 patients. A good correlation was found between birth weight and abdominal volume (r=0.77) and between birth weight and head volume (r=0.5). Correlation between bidimensional measurements and actual fetal weights was found to be comparable with previously published correlations. CONCLUSION: Volume measurements of the fetus may improve the accuracy of estimating fetal size. Additional studies using different volume measurement of the fetus are necessary.

First-trimester sonographic findings associated with a Dandy-Walker malformation and inferior vermian hypoplasia.

We report 2 cases in which first-trimester measurements of the intracranial translucency and the brain stem-to-occipital bone diameter were markedly enlarged. This finding was thought to represent an abnormal fourth ventricle-cisterna magna complex. Subsequently, the diagnoses of a Dandy-Walker malformation with partial vermian agenesis in 1 case and inferior vermian hypoplasia in the other were established and confirmed by either postmortem autopsy or postnatal magnetic resonance imaging. These cases suggest that evaluation of the fourth ventricle-cisterna magna complex, by measuring the intracranial translucency or brain stem-to-occipital bone diameter may identify some cases with structural malformations of the cerebellum as early as the first trimester.

NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits.

We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.

Elevated umbilical artery systolic/diastolic ratio in the absence of fetal growth restriction.

PURPOSE: To evaluate whether patients with isolated elevation of umbilical artery (UA) systolic/diastolic (S/D) ratio are at increased risk for adverse perinatal outcome. METHODS: This is a retrospective cohort study of 330 patients who underwent routine evaluation at our maternal fetal medicine center. We regularly perform UA S/D ratio analysis with every third trimester sonogram. All identified patients were included and divided into four groups based on estimated fetal weight (EFW) and UA S/D ratio. Perinatal outcome was compared between the groups. RESULTS: Regardless of the EFW, fetuses with persistent elevated UA S/D ratio showed significantly more preterm deliveries (p < .001), neonatal intensive care unit (NICU) admissions (p < .001), longer stay in the NICU (p < .001) and lower birth weight (p < .001) relative to controls. Stepwise logistic regression analysis demonstrated that being a member in any study group significantly and independently predicted birth weight less than the 10th percentile and preterm delivery. Patients with persistently elevated S/D ratio were significantly and independently from other factors, more likely to have a newborn admitted to the NICU. CONCLUSION: Our results indicate a suboptimal perinatal outcome in all pregnancies with an elevated UA S/D ratio. These fetuses may benefit from intensive monitoring.

Complete trisomy 21 vs translocation Down syndrome: a comparison of modes of ascertainment.

OBJECTIVE: To compare the indications for invasive prenatal testing resulting in the detection of translocation Down syndrome and complete trisomy 21. STUDY DESIGN: This case control study was based on a large amniocentesis and chorionic villi samples database (n = 534,795). All specimens with translocation Down syndrome (n = 203) comprised the translocation group and were compared with a maternal age-matched group (4 to 1, n = 812) in which complete trisomy 21 was detected. Women with a normal karyotype were randomly selected (n = 812) and served as controls. Indications for invasive testing were compared among the 3 paired groups using χ(2) analysis. RESULTS: There were no differences in the incidence of abnormal first- and second-trimester screening tests between the translocation Down syndrome and the complete trisomy 21 groups. History of prior aneuploidy was significantly more frequent in the translocation Down syndrome group, as compared with either complete trisomy 21 fetuses or normal controls. CONCLUSION: Fetuses with translocation Down syndrome present with the same screening abnormalities as fetuses with complete trisomy 21.