Mark W. Tomlinson

Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18.

OBJECTIVE We sought to evaluate performance of a noninvasive prenatal test for fetal trisomy 21 (T21) and trisomy 18 (T18). STUDY DESIGN A multicenter cohort study was performed whereby cell-free DNA from maternal plasma was analyzed. Chromosome-selective sequencing on chromosomes 21 and 18 was performed with reporting of an aneuploidy risk (High Risk or Low Risk) for each subject. RESULTS Of the 81 T21 cases, all were classified as High Risk for T21 and there was 1 false-positive result among the 2888 normal cases, for a sensitivity of 100% (95% confidence interval [CI], 95.5-100%) and a false-positive rate of 0.03% (95% CI, 0.002-0.20%). Of the 38 T18 cases, 37 were classified as High Risk and there were 2 false-positive results among the 2888 normal cases, for a sensitivity of 97.4% (95% CI, 86.5-99.9%) and a false-positive rate of 0.07% (95% CI, 0.02-0.25%). CONCLUSION Chromosome-selective sequencing of cell-free DNA and application of an individualized risk algorithm is effective in the detection of fetal T21 and T18.

Cell-free DNA Analysis for Noninvasive Examination of Trisomy

BACKGROUND Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations. METHODS In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Downs syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13. RESULTS Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001). CONCLUSIONS In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).

Does delivery improve maternal condition in the respiratory-compromised gravida?

Objective To describe the effect of delivery on respiratory status and outcome in the respiratory-compromised pregnant woman. Methods During 1990-1994, 10 patients requiring intubation for respiratory compromise who delivered during ventilatory support were identified by International Classification of Diseases, Ninth Revision codes. Charts were reviewed retrospectively for cardiorespiratory variables and outcome. Results Pneumonia led to intubation in all but one case. The onset of labor was spontaneous in eight. Three were delivered by cesarean. Mechanical ventilation was used for a median (range) of 7 (2-22) days in surviving patients. Fraction of inspired oxygen requirements decreased an average of 28% by 24 hours after delivery. Positive end-expiratory pressure requirements remained unaltered. Surviving patients remained intubated for a median (range) of 2.6 (1–19) days postpartum. Three women died, all after vaginal delivery (days 4–14). Conclusion Delivery of respiratory-compromised gravidas resulted in a 28% reduction in fraction of inspired oxygen requirement within 24 hours after delivery. Although most patients were then able to be maintained below critical fraction of inspired oxygen requirement levels (under 0.6), dramatic improvement in overall respiratory function was not observed uniformly. Given the limited benefit of delivery on maternal oxygenation, along with the inherent risks of labor induction in this critically ill population, caution should be exercised in initiating the induction process electively.

Isolated Mild Ventriculomegaly : Associated Karyotypic Abnormalities and In Utero Observations

OBJECTIVE The incidence of abnormal chromosomes in fetuses with mild lateral ventriculomegaly as an isolated prenatal ultrasound finding is not well established, and the rate of progression to more severe ventriculomegaly is uncertain. We wished to better define both the incidence of karyotypic abnormalities and the in utero course of fetuses with isolated mild ventriculomegaly. SUBJECTS AND METHODS From July 1992 to September 1994, all cases of mild ventriculomegaly at our institution were reviewed (N = 94). Forty-six were isolated. Of these, 25 had genetic evaluation, and 37 had serial ultrasound examination. We evaluated the frequencies of karyotype abnormality and in utero progression for atrial measurements of 11-15 mm. RESULTS In fetuses with atria 11-15 mm, three of the 25 karyotypes were abnormal (47 XXY and two 47 + 21, giving an incidence of 12% (95% CI 4.2-30.1%). Of the 37 with serial scans, five resolved in utero, 11 remained unchanged, and 20 progressed (one beyond 15 mm). CONCLUSION Isolated mild ventriculomegaly is associated with a significantly increased incidence of chromosomal abnormalities. Therefore, these patients should be offered genetic testing. When mild and isolated, some fetuses will show in utero resolution of the ventriculomegaly. Progression to more severe degrees of hydrocephalus is uncommon.

Vascular Disruption Birth Defects and History of Prenatal Cocaine Exposure: A Case Control Study

OBJECTIVE To test the hypothesis that prenatal cocaine exposure is associated with a 3-fold increased risk for vascular disruption among malformations. STUDY DESIGN A retrospective case-control study was based upon >68,000 delivery records at Hutzel Hospital for a 9-year period. Ascertainment was based upon ICD-9 codes for limb defects, abdominal wall defects, and facial clefts. Transverse limb defects and gastroschisis were defined as cases, and nondisruption anomalies served as controls. Statistical analysis for history of maternal cocaine use reported during pregnancy was performed by chi(2) analysis and the odds ratio determined. RESULTS A total of 190 cases of limb anomalies, abdominal wall defects, and cleft lips were identified after exclusion criteria. Statistical analysis was performed on the 119 cases informative for maternal cocaine use during pregnancy. Seven of 34 vascular disruption cases had cocaine exposure reported versus 12 of 85 other malformations controls. The odds ratio for cocaine exposure and vascular disruption is 1.58 (95% confidence interval = 0.55-4.47). CONCLUSION The putative association of prenatal cocaine exposure and vascular disruption birth defects remains unresolved, but the attributable risk is very likely less than the 3-fold odds ratio previously reported.

Delayed umbilical cord clamping in premature neonates.

OBJECTIVE: Delayed umbilical cord clamping is reported to increase neonatal blood volume. We estimated the clinical outcomes in premature neonates who had delayed umbilical cord clamping compared with a similar group who had early umbilical cord clamping. METHODS: This was a before–after investigation comparing early umbilical cord clamping with delayed umbilical cord clamping (45 seconds) in two groups of singleton neonates, very low birth weight (VLBW) (401–1,500 g) and low birth weight (LBW) (greater than 1,500 g but less than 35 weeks gestation). Neonates were excluded from delayed umbilical cord clamping if they needed immediate major resuscitation. Primary outcomes were provision of delivery room resuscitation, hematocrit, red cell transfusions, and the principle Vermont Oxford Network outcomes. RESULTS: In VLBW neonates (77 delayed umbilical cord clamping, birth weight [mean±standard deviation] 1,099±266 g; 77 early umbilical cord clamping 1,058±289 g), delayed umbilical cord clamping was associated with less delivery room resuscitation, higher Apgar scores at 1 minute, and higher hematocrit. Delayed umbilical cord clamping was not associated with significant differences in the overall transfusion rate, peak bilirubin, any of the principle Vermont Oxford Network outcomes, or mortality. In LBW neonates (172 delayed umbilical cord clamping, birth weight [mean±standard deviation] 2,159±384 g; 172 early umbilical cord clamping 2,203±447 g), delayed umbilical cord clamping was associated with higher hematocrit and was not associated with a change in delivery room resuscitation or Apgar scores or with changes in the transfusion rate or peak bilirubin. Regression analysis showed increasing gestational age and birth weight and delayed umbilical cord clamping were the best predictors of higher hematocrit and less delivery room resuscitation. CONCLUSION: Delayed umbilical cord clamping can safely be performed in singleton premature neonates and is associated with a higher hematocrit, less delivery room resuscitation, and no significant changes in neonatal morbidities. LEVEL OF EVIDENCE: II

Extremely premature birth and the choice of neonatal intensive care versus palliative comfort care: an 18-year single-center experience

Objective:Review all live births 22 0/7 through 26 6/7 weeks gestation born 1996 through 2013 at our institution to describe the decision process and immediate outcomes of palliative comfort care (PCC) versus neonatal intensive care (NICU) and whether any significant family complaints or quality assurance concerns arose.Study Design:Retrospective chart review, physician and ethicist interview process and database review focused upon our established periviability counseling guidelines that are directive of PCC at 22 weeks gestation and NICU at 26 weeks but supportive of informed family choice of either option at 23, 24 and 25 weeks.Result:At 22 weeks—all 54 infants had PCC; at 23 weeks—29/78 (37%) chose NICU care, 6/29 (21%) infants survived; at 24 weeks—79/108 (73%) chose NICU care, 47/79 (59%) survived; at 25 weeks—147/153 (96%) chose NICU care, 115/147 (78%) survived; and at 26 weeks—all infants had NICU care, 176/203 (87%) survived. Over 18 years and 606 births, we identified only three significant concerns from families and/or physicians that required formal review.Conclusion:Most pregnant women and families choose NICU care for their extremely premature infant, but if given the option via shared decision making, a significant proportion will choose PCC at gestational ages that some NICUs mandate resuscitation. We support a reasoned dialogue and bioethical framework that recognizes human values to be irreducibly diverse, sometimes conflicting, and ultimately incommensurable—value pluralism. Respectful shared decision making requires thoughtful and compassionate flexibility, nuanced and individualized suggestions for PCC or NICU and the reduction of hierarchical directives from physicians to families. We continue to advocate and rely upon informed family preference between 23 and 25 weeks gestation in our updated 2015 periviability guidelines.

Oregon's Hard-Stop Policy Limiting Elective Early-Term Deliveries: Association With Obstetric Procedure Use and Health Outcomes.

OBJECTIVE: To evaluate the association of Oregons hard-stop policy limiting early elective deliveries (before 39 weeks of gestation) and the rate of elective early-term inductions and cesarean deliveries and associated maternal–neonatal outcomes. METHODS: This was a population-based retrospective cohort study of Oregon births between 2008 and 2013 using vital statistics data and multivariable logistic regression models. Our exposure was the Oregon hard-stop policy, defined as the time periods prepolicy (2008–2010) and postpolicy (2012–2013). We included all term or postterm, cephalic, nonanomalous, singleton deliveries (N=181,034 births). Our primary outcomes were induction of labor and cesarean delivery at 37 or 38 weeks of gestation without a documented indication on the birth certificate (ie, elective early term delivery). Secondary outcomes included neonatal intensive care unit admission, stillbirth, macrosomia, chorioamnionitis, and neonatal death. RESULTS: The rate of elective inductions before 39 weeks of gestation declined from 4.0% in the prepolicy period to 2.5% during the postpolicy period (P<.001); a similar decline was observed for elective early-term cesarean deliveries (from 3.4% to 2.1%; P<.001). There was no change in neonatal intensive care unit admission, stillbirth, or assisted ventilation prepolicy and postpolicy, but chorioamnionitis did increase (from 1.2% to 2.2%, P<.001; adjusted odds ratio 1.94, 95% confidence interval 1.80–2.09). CONCLUSIONS: Oregons statewide policy to limit elective early-term delivery was associated with a reduction in elective early-term deliveries, but no improvement in maternal or neonatal outcomes.

Severe pre-eclampsia remote from term: what to expect of expectant management

Objective: To describe the duration of expectant management and the indications for termination of expectant management of pregnancies complicated by severe pre-eclampsia remote from term. Study design: We identified pregnancies complicated by severe pre-eclampsia diagnosed between 24 weeks and 31 weeks 6 days at our institution in 1991-98. Pertinent clinical data were obtained from review of maternal and neonatal charts. Comparison of patients was based on the duration of time from admission to delivery: < 48 h (group 1), 48 h to 7 days (group 2), and ≥ 7 days (group 3). Results:A total of 142 women met all study criteria. Seventy-nine (55.6%) women were delivered within 48 h, 42 (29.6%) between 48 h and 7 days, and 21 (14.8%) at ≥ 7 days from diagnosis. Of group 1 patients (< 48 h), 59 (74.7%) were delivered for maternal indications while 20 (25.3%) were delivered for fetal indications. Of group 2 patients (48 h to 7 days), 35 (83.3%) were delivered for maternal indications while seven (16.7%) were delivered for fetal indications. Of group 3 patients (≥ 7 days), 16 (76.2%) were delivered for maternal indications while five (23.8%) were delivered for fetal indications. There were no significant differences in the indications for delivery based on the duration from admission to delivery. Conclusions: Despite an aggressive approach towards expectant management of preterm pregnancies complicated by severe pre-eclampsia, most patients were delivered within 48 h for maternal indications.

Correction of Hemodynamic Abnormalities by Vesicoamniotic Shunting in Familial Congenital Megacystis

Vesicoamniotic shunting is typically reserved for treatment of fetal obstructive uropathy. We report a case of congenital megacystis without anatomic urinary obstruction in whom a vesicoamniotic shunt was used to improve fetal hemodynamics as measured by Doppler velocimetry.