Booster course of antenatal corticosteroids after preterm prelabor rupture of membranes: a double-blind randomized trial.

BACKGROUND: Preterm prelabor rupture of membranes is a leading cause of preterm birth and is responsible for 18% to 20% of perinatal deaths in the United States. An initial course of antenatal corticosteroids has been shown to reduce morbidity and mortality in patients with preterm prelabor rupture of membranes. For patients who remain undelivered for 7 days or more after the initial course of antenatal corticosteroids, it is uncertain whether a booster course of antenatal corticosteroids reduces neonatal morbidity or increases the infection risk. The American College of Obstetricians and Gynecologists has concluded that the current evidence is insufficient to make a recommendation. OBJECTIVE: This study aimed to evaluate if a single booster course of antenatal corticosteroids improves neonatal outcomes after preterm prelabor rupture of membranes. STUDY DESIGN: We conducted a multicenter, placebo-controlled randomized clinical trial. The inclusion criteria were preterm prelabor rupture of membranes, gestational age of 24.0 to 32.9 weeks, singleton, initial antenatal corticosteroid course administered at least 7 days before randomization, and planned expectant management. Consenting patients were randomized in gestational age blocks to either receive booster antenatal corticosteroids (12 mg betamethasone every 24 hours for 2 days) or a saline placebo. The primary outcome was composite neonatal morbidity or death. A sample size of 194 patients was calculated to yield 80% power at P<.05 to detect a reduction in primary outcome from 60% in placebo group to 40% in antenatal corticosteroids group. RESULTS: From April 2016 through August 2022, 194 patients consented and were randomized (47% of 411 eligible patients). Intent-to-treat analysis was performed on 192 patients (2 placebo patients left hospital, outcomes unknown). The groups had similar baseline characteristics. The primary outcome occurred in 64% of patients who received booster antenatal corticosteroids vs in 66% of patients who received the placebo (odds ratio, 0.82; 95% confidence interval, 0.43-1.57; gestational age-stratified Cochran-Mantel-Haenszel test). Individual components of the primary outcome and secondary neonatal and maternal outcomes were not significantly different between the antenatal corticosteroids and placebo groups. Specifically, chorioamnionitis (22% vs 20%), postpartum endometritis (1% vs 2%), wound infections (2% vs 0%), and proven neonatal sepsis (5% vs 3%) were not different between the groups. CONCLUSION: A booster course of antenatal corticosteroids at least 7 days after the first antenatal corticosteroids course in patients with preterm prelabor rupture of membranes did not improve neonatal morbidity or any other outcome in this adequately-powered, double-blind randomized clinical trial. Booster antenatal corticosteroids did not increase maternal or neonatal infection.

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.

Cervical Pessary versus Expectant Management for the Prevention of Delivery Prior to 36 Weeks in Women with Placenta Previa: A Randomized Controlled Trial.

Objective This multicenter randomized controlled trial compared cervical pessary (CP) versus expectant management (EM) in women with placenta previa between 22.0 and 32.0 in prolonging gestation until ≥ 36.0 weeks' gestation. Study Design This study took place from November 2016 to June 2018. Women were randomized to receive either the Bioteque CP or EM. The pessary was removed at ≥ 36.0 weeks unless indicated. The primary outcome was gestational age (GA) at delivery, with secondary outcomes including need for transfusion, number and duration of antepartum admissions, type of delivery, and neonatal outcomes. A total of 140 patients were needed to show a 3-week prolongation of pregnancy in the pessary group; however, the trial was stopped early due to budgetary issues. Results Of the 33 eligible women, 17 were enrolled. Although not statistically significant, the mean GA at delivery in the CP group was greater than women in the EM group (36.5 ± 1.23 vs. 36.0 ± 2.0; p = 0.1673). The number and duration of antepartum admissions was greater in the EM group (2.7 ± 0.58 vs. 16.0 ± 22.76 days; p = 0.1264) as well. Conclusion Although the study was underpowered to determine the primary outcome, safety and feasibility of CP in pregnancies complicated with previa were demonstrated.

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.

A multicenter prospective study of neonatal outcomes at less than 32 weeks associated with indications for maternal admission and delivery.

BACKGROUND: Counseling for patients with impending premature delivery traditionally has been based primarily on the projected gestational age at delivery. There are limited data regarding how the indications for the preterm birth affect the neonatal outcome and whether this issue should be taken into account in decisions regarding management and patient counseling. OBJECTIVE: We performed a prospective study of pregnancies resulting in premature delivery at less than 32 weeks to determine the influence of both the indications for admission and their associated indications for delivery on neonatal mortality and complications of prematurity. STUDY DESIGN: This is a multicenter, prospective study in 10 hospitals where all data from the neonatal intensive care unit routinely was imported to a deidentified data warehouse. Maternal data were collected prospectively at or near the time of delivery. Eligible subjects included singleton deliveries in these hospitals between 23 0/7 and 31 6/7 weeks. The primary hypothesis of the study was to determine whether there was a difference in the primary outcome, which was defined as neonatal composite morbidity, between those neonates delivered after admission for premature labor vs premature rupture of membranes, because these were expected to be the 2 most frequent diagnoses leading to premature birth. The sample size was calculated based on a 10% difference in outcomes for these 2 entities. We based this hypothesis on the knowledge that premature rupture of membranes has a greater incidence of intra-amniotic infection and inflammation than premature labor and that outcomes for premature neonates are worse when delivery is associated with intra-amniotic infection. Additional outcomes were analyzed for all other indications for admission and delivery. Composite morbidity was defined as ≥1 of the following: respiratory distress syndrome (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 28 days of life), severe intraventricular hemorrhage (grades 3 or 4), periventricular leukomalacia, blood culture-proven sepsis present within 72 hours of birth, necrotizing enterocolitis, or neonatal death before discharge from the hospital. A secondary composite of serious neonatal morbidity also was defined prospectively. RESULTS: The study included 1089 mother/baby pairs. Composite morbidity between those with premature labor (77.2%) and premature rupture of membranes (73.2%) was not significantly different (P = .29). A few neonatal complications were associated with indications for admission and delivery, but on logistic regression adjusting for gestational age and other confounders, suspected intrauterine growth restriction was the only indication for admission or delivery associated with an increase in serious morbidity (odds ratio 4.5, [2.1 to 9.8], P < .003). Other factors not related to the indications for admission including cesarean delivery, and low 5-minute Apgar were associated with an increase in morbidity. CONCLUSION: Studies of many single factors related to the indications for preterm delivery have been shown to be associated with adverse neonatal outcome. In this study evaluating all of the most frequent indications, however, we found only suspected intrauterine growth restriction as an indication for admission and delivery was found to be so. Thus, it seems that in almost all situations counseling patients can be based primarily on gestational age along with other factors including estimated fetal weight, sex, race, plurality, and completion of a course of antenatal corticosteroids.

17-hydroxyprogesterone caproate for preterm rupture of the membranes: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS: From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION: Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.

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.

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes.

OBJECTIVE: The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes. STUDY DESIGN: Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). RESULTS: The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively). CONCLUSION: We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

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.

17-Hydroxyprogesterone caproate to prolong pregnancy after preterm rupture of the membranes: early termination of a double-blind, randomized clinical trial.

BACKGROUND: Progestational agents may reduce the risk of preterm birth in women with various risk factors. We sought to test the hypothesis that a weekly dose of 17-hydroxyprogesterone caproate (17P) given to women with preterm rupture of the membranes (PROM) will prolong pregnancy and thereby reduce neonatal morbidity. METHODS: Double-blind, placebo-controlled randomized clinical trial. Women with PROM at 23.0 to 31.9 weeks of gestation were randomly assigned to receive a weekly intramuscular injection of 17P (250 mg in 1 mL castor oil) or placebo (1 mL castor oil). The primary outcome was the rate of continuing the pregnancy until 34.0 weeks of gestation or until documentation of fetal lung maturity at 32.0 to 33.9 weeks of gestation. Planned secondary outcomes were duration of latency period and rate of composite neonatal morbidity. Enrollment of 111 participants per group, 222 total, was planned to yield 80% power to detect an increase in the primary outcome from 30% with placebo to 50% with 17P. RESULTS: Twelve women were enrolled of whom 4 were randomly assigned to receive 17P and 8 to receive placebo. The trial was terminated prematurely because of two separate issues related to the supply of 17P. No adverse events attributable to 17P were identified. CONCLUSION: Because of premature termination, the trial does not have adequate statistical power to evaluate efficacy or safety of 17P in women with PROM. Nonetheless, ethical principles dictate that we report the results, which may contribute to possible future metaanalyses and systematic reviews. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119963Supported by a research grant from the Center for Research, Education, and Quality, Pediatrix Medical Group, Sunrise, FL.

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.

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.

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.

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.