Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA.

OBJECTIVE: The objective of this study was to validate the clinical performance of massively parallel genomic sequencing of cell-free deoxyribonucleic acid contained in specimens from pregnant women at high risk for fetal aneuploidy to test fetuses for trisomies 21, 18, and 13; fetal sex; and the common sex chromosome aneuploidies (45, X; 47, XXX; 47, XXY; 47, XYY). STUDY DESIGN: This was a prospective multicenter observational study of pregnant women at high risk for fetal aneuploidy who had made the decision to pursue invasive testing for prenatal diagnosis. Massively parallel single-read multiplexed sequencing of cell-free deoxyribonucleic acid was performed in maternal blood for aneuploidy detection. Data analysis was completed using sequence reads unique to the chromosomes of interest. RESULTS: A total of 3430 patients were analyzed for demographic characteristics and medical history. There were 137 fetuses with trisomy 21, 39 with trisomy 18, and 16 with trisomy 13 for a prevalence rate of the common autosomal trisomies of 5.8%. There were no false-negative results for trisomy 21, 3 for trisomy 18, and 2 for trisomy 13; all 3 false-positive results were for trisomy 21. The positive predictive values for trisomies 18 and 13 were 100% and 97.9% for trisomy 21. A total of 8.6% of the pregnancies were 21 weeks or beyond; there were no aneuploid fetuses in this group. All 15 of the common sex chromosome aneuploidies in this population were identified, although there were 11 false-positive results for 45,X. Taken together, the positive predictive value for the sex chromosome aneuploidies was 48.4% and the negative predictive value was 100%. CONCLUSION: Our prospective study demonstrates that noninvasive prenatal analysis of cell-free deoxyribonucleic acid from maternal plasma is an accurate advanced screening test with extremely high sensitivity and specificity for trisomy 21 (>99%) but with less sensitivity for trisomies 18 and 13. Despite high sensitivity, there was modest positive predictive value for the small number of common sex chromosome aneuploidies because of their very low prevalence rate.

The senior obstetrician requesting obstetric privileges.

As the American physician workforce matures in age, senior physicians on the active clinical staff may become vulnerable to diminished professional performance. Many physicians compensate by using experiential rather than analytic methods to effectively solve clinical problems. Surgical expertise also may be at risk in these circumstances. Organized medical staffs must confront these realities before adverse events are reported as patient safety is their primary responsibility. The appropriate credentialing process will enable talented and experienced senior clinicians to continue to provide high quality medical care.

Surgical remedies for postpartum hemorrhage.

When medical therapy is unsuccessful, surgical approaches to postpartum hemorrhage are often considered. These may include uterine curettage, laceration repair, balloon tamponade, compressive suture techniques, uterine or hypogastric artery ligation, and ultimately hysterectomy. A systems approach to the care of these patients includes identification of rapid response teams, assessment of risk factors, and the timely and knowledgeable use of blood and blood products. Comprehensive care of patients with massive obstetric hemorrhage will improve the outcome of this largely preventable cause of maternal mortality.

Evaluation of a novel screening method for fetal aneuploidy using cell-free DNA in maternal plasma.

Objective: To evaluate the test performance of a novel sequencing technology using molecular inversion probes applied to cell-free DNA screening for fetal aneuploidy. Methods: Two cohorts were included in the evaluation; a risk-based cohort of women receiving diagnostic testing in the first and second trimesters was combined with stored samples from pregnancies with fetuses known to be aneuploid or euploid. All samples were blinded to testing personnel before being analyzed, and validation occurred after the study closed and results were merged. Results: Using the new sequencing technology, 1414 samples were analyzed. The findings showed sensitivities and specificities for the common trisomies and the sex chromosome aneuploidies at >99% (Trisomy 21 sensitivity 99.2 CI 95.6­99.2; specificity 99.9 CI 99.6­99.9). Positive predictive values among the trisomies varied from 85.2% (Trisomy 18) to 99.0% (Trisomy 21), reflecting their prevalence rates in the study. Comparisons with a meta-analysis of recent cell-free DNA screening publications demonstrated equivalent test performance. Conclusion: This new technology demonstrates equivalent test performance compared with alternative sequencing approaches, and demonstrates that each chromosome can be successfully interrogated using a single probe.

The changing specter of uterine rupture.

OBJECTIVE: The objective of the study was to review all patient records discharged with codes for uterine rupture in 2006 in Hospital Corporation of America hospitals. STUDY DESIGN: All patient charts were distributed to a committee of perinatologists and general obstetricians. Case report forms were analyzed for variables of interest to determine validity of coding and quality of care. RESULTS: Of 69 cases identified, only 41 were true ruptures. Twenty patients had previous cesareans, and in 9 of these patients, concurrent use of oxytocics was documented. Among the 21 patients without previous cesareans, 7 had previous uterine surgery, and oxytocics were documented in 12 of the remaining 14 patients. Standard of care violations were identified in 10 of 41 true rupture cases. CONCLUSION: Epidemiological data on uterine rupture based on hospital discharge codes without concurrent chart review may be invalid. Patients with previous cesareans represent only half of true uterine ruptures in contemporary practice.

Immunogenesis of preeclampsia: lessons from donor gametes.

BACKGROUND: Preeclampsia remains an important complication of pregnancy. It is associated with mortality and morbidity for both maternal and fetal/newborn patients. Although major inroads have been made in understanding the pathophysiology of preeclampsia in recent decades, the initial primary cause of its occurrence in some women and not others has escaped clarification. REVIEW: There have been a number of clinical clues pointing to an immune genesis of this disease, including most recently the use of donor gametes in assisted reproductive technology (ART). Despite a number of confounding variables, most studies investigating the addition of donor ova to the ART environment point in the direction of an immune genesis due to the burden of an increasingly foreign fetal allograft on the maternal host. A review of a selection of these studies and a contemporary review of our own Maternal Fetal Medicine practice observations in this regard was completed. CONCLUSIONS: This retrospective evidence suggests a highly likely association. A more basic understanding of the immune interactions at the maternal-fetal interface is required before a final solution to this problem will be at hand and targeted remedies can be formulated.

Cesarean birth in the morbidly obese woman: a report of 3 cases.

BACKGROUND: Primary and repeat cesarean births are a frequent occurrence among morbidly obese women. Technical difficulties encountered in caring for these patients, coupled with physiologic differences, affect their operative management. CASES: Three morbidly obese women (190-296 kg, body mass index 56.7-93.6) had cesarean births utilizing a supraumbilical incision and internal retention abdominal wall closures. Alternative anesthetic management was required in 2 patients. Bariatric operative and postoperative equipment was required in each case, and varying thromboprophylaxis strategies were employed. CONCLUSION: Careful planning along with appropriate specialty consultation is required for a safe and successful cesarean birth in the morbidly obese woman.

Peripartum intensive care.

OBJECTIVE: To determine the prevalence rate of intensive care unit (ICU) admissions in Hospital Corporation of America (HCA) hospitals and further delineate indications and outcomes in a retrospective review at one such hospital. STUDY DESIGN: Diagnosis-related group and revenue codes were combined to calculate maternity admissions to the ICU in HCA hospitals. Prospectively logged maternal admissions were retrospectively reviewed for calendar years 2004-2008 at Presbyterian/St. Luke's Medical Center (PSL) using inpatient medical records. RESULTS: The prevalence rate of peripartum ICU admissions in HCA hospitals among 602,488 deliveries was 0.41%. At PSL, a high-acuity maternal fetal service, the occurrence of ICU admissions was 0.62%. Leading indications were hemorrhage and preeclampsia/eclampsia; multiples were over-represented, 20% required hysterectomy and nearly one-third of the patients were ventilated. CONCLUSIONS: The full scope of ICU resources should be available to the obstetric patient as the maternal requirement for such care is not rare.

Amniocentesis in the management of preterm premature rupture of the membranes: a retrospective cohort analysis.

OBJECTIVE: This retrospective analysis determined the utility of amniocentesis in the management of preterm premature rupture of the membranes (PPROM). STUDY DESIGN: Consecutive patients with PPROM were managed with and without amniocentesis. Both groups received antibiotics and corticosteroids; tocolytics were withheld. Patients were induced if clinical or amniotic fluid (AF) proven chorioamnionitis occurred or gestational age goals were reached. Primary endpoints were individual and composite neonatal morbidity (CNM). RESULTS: One hundred forty-seven maternal patients were managed with amniocentesis (AC) and 146 were managed without amniocentesis (NAC). CNM was significantly reduced in the group managed with AC (OR 2.94, 95% CI 1.68-5.15, NAC vs. AC). NAC patients had similar rates of neonatal sepsis as well as CNM to those patients in the AC group with positive AF Gram stains and/or cultures. CONCLUSIONS: Patients with PPROM who are managed with AC have significantly less CNM than NAC patients.

Expectation of pregnancy outcome among mature women.

OBJECTIVE: Increasing numbers of mature women are achieving pregnancy largely through assisted reproductive technology (ART). Our objective was to investigate women over 45 years of age to determine the impact of pregnancy complications on newborn outcome. STUDY DESIGN: A study of women older than 45 years at their estimated date of confinement (EDC) was compared with a control group under 36 years at their EDC, matched by parity and plurality. All study patients and controls received uniform obstetric management through a single maternal fetal practice. The primary outcome was gestational age at birth stratified by plurality; secondary outcomes included birth weight, NICU days, composite neonatal morbidity, and a variety of obstetric complications. Wilcoxon signed rank and McNemar's tests were used as appropriate; logistic regression was used to calculate odds ratios (ORs) and CIs. Statistical significance was assumed for P < .05. RESULTS: Fifty study and control patients were identified over a 5-year period. Study patients were older than controls, but the difference in "gamete" age was not significant. There was significantly more assisted reproduction (donor egg) and preeclampsia among study patients. Importantly, gestational age at birth and birth weights stratified by plurality were not different (86% power to detect 2-week gestational age difference, alpha 0.05). Hospital days, NICU days, and composite neonatal morbidity were not different between study patients and controls. CONCLUSION: When controlled for parity and plurality, mature women over 45 years conceiving largely through ART with donor eggs can expect newborn outcomes similar to younger women cared for in the same setting of a high-risk maternal-fetal practice.

Improved perinatal survival of monoamniotic twins with intensive inpatient monitoring.

OBJECTIVE: The purpose of this study was to evaluate the impact of routine hospitalization for fetal monitoring on the perinatal survival and neonatal morbidity of monoamniotic twins. STUDY DESIGN: This was a multicenter retrospective cohort analysis of 96 monoamniotic twin gestations from 11 university and private perinatal practices. Overall mortality rates were calculated. The risk of intrauterine fetal death and neonatal morbidity was compared among women who were observed as inpatients versus outpatients. RESULTS: The overall mortality rate from enrollment was 19.8% (mean gestational age at enrollment, 17.4 weeks). The perinatal mortality and corrected perinatal mortality rates were 15.4% and 12.6%, respectively. Eighty-seven women had both twins who were surviving at 24 weeks of gestation; 43 women were admitted electively for inpatient surveillance at a median gestational age of 26.5 weeks; the remainder of the women were followed as outpatients and admitted only for routine obstetric indications (median gestational age, 30.1 weeks). No intrauterine fetal deaths occurred in any hospitalized patient. The risk of intrauterine fetal death in women who were followed as outpatients was 14.8% (13/88) versus 0 for women who were followed as inpatients (P < .001). There also were statistically significant improvements in birth weight, gestational age at delivery, and neonatal morbidity for women who were followed as inpatients. CONCLUSION: We observed improved neonatal survival and decreased perinatal morbidity among women who were admitted electively for inpatient fetal monitoring.

Percutaneous ultrasonographically guided ablation of an acardiac twin.

Acardiac twinning is caused by twin reversed arterial perfusion (TRAP). Normal "pump" twins may face early delivery and cardiac decompensation and have a high perinatal mortality. A primagravid patient had serial evaluation of a TRAP pregnancy beginning early in the second trimester. Rapid growth of the acardiac sibling, high diastolic velocity Doppler waveforms in the perfusing vessel, and early hydramnios prompted ablation of blood flow by a percutaneous ultrasonographically guided infusion of absolute alcohol. A term birth of a normal pump twin was the outcome. Ablation of blood flow into an acardiac sibling of a TRAP pregnancy may be indicated in cases with a poor prognosis by use of an effective percutaneous ultrasonographically guided technique.

Selective fetocide reverses preeclampsia in discordant twins.

OBJECTIVE: Preeclampsia occurs in some twin gestations in association with a placental disorder of one but not both fetuses, thereby placing both at risk. We investigated a novel method of treating preeclampsia in these pregnancies. STUDY DESIGN: Three patients with second trimester preeclampsia linked to a lethal condition in one twin were treated with selective fetocide in an effort to reverse preeclampsia. Two patients presented with twins discordant for severe fetal growth restriction, and 1 patient presented with Ballantyne syndrome and twins discordant for fetal hydrops. RESULTS: Preeclampsia resolved in all 3 patients, allowing continuation of the pregnancy for an additional 9 to 23 weeks before delivery of the remaining fetus. Resolution of preeclampsia occurred in a timeframe consistent with placental involution documented in similar clinical circumstances. CONCLUSION: Selective fetocide may be an option for treating preeclampsia in some twin pregnancies, presumably by causing involution of the pathologic placenta. Delivery is not the only cure for preeclampsia.

Dystocia in nulliparous patients monitored with fetal pulse oximetry.

OBJECTIVE: A critical analysis of the United States randomized controlled trial of fetal pulse oximetry concluded that nonreassuring fetal heart rate patterns used for study entry may have been a marker for dystocia. We prospectively studied nulliparous women in labor whose progress was monitored with fetal pulse oximetry to examine the relationship between nonreassuring fetal heart rate patterns and operative delivery for dystocia. STUDY DESIGN: A prospective nonrandomized observational cohort study compared two distinct classes of nonreassuring fetal heart rate patterns (class I: intermittent, mildly nonreassuring; class II: persistent, progressive, and moderate to severely nonreassuring) among nulliparous patients with the use of fetal pulse oximetry to confirm fetal well-being. Definitions of dystocia included the cessation of labor progress in the first (3 hours) or second (2 hours) stage of labor, despite adequate uterine activity that was assessed with an intrauterine pressure catheter. Independent review confirmed the classification of nonreassuring fetal heart rate patterns and study entry criteria. RESULTS: Two hundred seventy-four patients met study criteria and had sufficient information for fetal heart rate tracing interpretation. Two hundred thirty-seven patients (86.5%) were class II, and 37 patients (13.5%) were class I. The two classes of patients were comparable in a variety of obstetric, demographic, and perinatal variables. Twelve percent of all patients were delivered for nonreassuring fetal status. Significantly more class II patients (22%) were delivered by cesarean for dystocia than were class I patients (8%). Higher doses and a longer number of hours of oxytocin were required among class II patients. Significantly more occiput posterior positions were noted among all patients who underwent cesarean delivery for dystocia compared with other modes of delivery. CONCLUSION: Significantly nonreassuring fetal heart rate patterns predict cesarean delivery for dystocia among nulliparous patients with normally oxygenated fetuses in a setting of a standardized labor management protocol. This confirms the observations in the randomized controlled trial of fetal pulse oximetry in the United States and may provide insight into the treatment of nonprogressive labor in contemporary practice.