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BackgroundPreterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective.ObjectiveTo determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc).Search strategyWe searched literature databases, trial registries and references in published articles.Selection criteriaRandomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies.Data collection and analysisInvestigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at

Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.

ObjectiveCorticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. During pregnancy corticotropin-releasing hormone is synthesized in large amounts by the placenta and released into the maternal and fetal circulations. Various endocrine, autocrine, and paracrine roles have been suggested for placental corticotropin-releasing hormone. The aim of this study was to prospectively assess the relationship between maternal plasma concentrations of corticotropin-releasing hormone in the early third trimester of pregnancy and the length of gestation in two groups of deliveries, with and without spontaneous labor.Study designIn a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples were collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record.ResultsMaternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length.ConclusionThese findings support the premise that placental corticotropin-releasing hormone is potentially implicated in the timing of human delivery in at least two ways. First, placental corticotropin-releasing hormone may play a role in the physiology of parturition. Premature or accelerated activation of the placental corticotropin-releasing hormone system, as reflected by precocious elevation of maternal corticotropin-releasing hormone levels, may therefore be associated with earlier onset of spontaneous labor and resultant delivery. Second, placental corticotropin-releasing hormone may be a marker of antepartum risk for preterm delivery and therefore an indirect predictor of earlier delivery. The implications of these findings are discussed in the context of the neuroendocrinology of placental corticotropin-releasing hormone and human parturition. Furthermore, the role of corticotropin-releasing hormone as a possible effector of prenatal stress in producing alterations in the timing of normal delivery is detailed.

In a prospective study, third trimester plasma levels of BE and ACTH were determined in 58 women who delivered vaginally. Peptide regulation was compared between subjects who used conduction anesthesia at delivery and subjects who did not. Third trimester levels of maternal BE and ACTH were significantly related; however, the relationship was significant only in subjects who did not receive conduction anesthesia (n = 24) at delivery. The normal co-release pattern between BE and ACTH in subjects receiving conduction anesthesia (n = 34) during birth was uncoupled. The use of conduction analgesia during vaginal delivery was significantly related to a disregulation index created to quantify the BE-ACTH release pattern. Uncoupled ACTH and BE patterns may result from modified control of pro-opiomelanocortin (POMC) expression during pregnancy or unique proteolytic processing of POMC, and may alter pain tolerance during delivery.

ObjectiveThe aim was to test a model of the influence of maternal prenatal psychosocial stress on birth outcomes after controlling for biomedical risk.Study designIn a prospective study a sociodemographically homogeneous sample of 90 women was assessed during the third trimester with standard, reliable questionnaires that measured episodic and chronic stress, strain (response to stress), and pregnancy-related anxiety. Birth outcomes included infant birth weight, gestational age at birth, and intrapartum complications. Parity and biomedical (antepartum) risk was also coded. Bivariate and multivariate analyses were performed after controlling for the effects of biomedical risk factors.ResultsIndependent of biomedical risk, each unit increase of prenatal life event stress (from a possible sample range of 14.7 units) was associated with a 55.03 gm decrease in infant birth weight and with a significant increase in the likelihood of low birth weight (odds ratio 1.32), and each unit increase of prenatal pregnancy anxiety (from a possible sample range of 5 units) was associated with a 3-day decrease in gestational age at birth.ConclusionIndependent of biomedical risk, maternal prenatal stress factors are significantly associated with infant birth weight and with gestational age at birth.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Information on outcome by gestational age from large numbers of twins and triplets is limited and is important for counseling and decision-making in obstetric practice. We reviewed one of the largest available neonatal databases to describe mortality and morbidity rates and growth in newborn infants from multiple gestations and compared these data with data for singletons. STUDY DESIGN: Data from a large prospectively recorded neonatal database that incorporated neonatal records from January 1997 to July 2002 were reviewed. We evaluated birth weight and neonatal mortality and morbidity rates that affected long-term outcome for each week of gestational age from 23 to 35 weeks of gestation for all nonanomolous inborn twins and triplets who were admitted to the neonatal intensive care unit and compared these data to all singletons who met similar criteria during the same time period. RESULTS: There were 12,302 twin and 2155 triplet births that met the entry criteria. The data for these newborn infants were compared with 36,931 singletons. Average birth weights at each gestational week were similar for all gestational ages until 29 weeks of gestation for triplets and 32 weeks of gestation for twins. After these gestational ages, the entire difference between twins and singletons was due to the weight of the smaller twin; the larger twins' mean weights were similar to singletons at all weeks that were studied. Birth order at each week also did not affect neonatal mortality rates, even when corrected for route of delivery and antenatal steroids. Neonatal morbidities associated with adverse long-term outcomes (intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis) were also not different between multiple infants and singletons. Intrauterine growth restriction (IUGR) was associated with increased mortality rates at all gestational ages, but in the absences of IUGR, discordance was not. CONCLUSION: Data on a large number of twins and triplets provide reassurance that neonatal outcome at all viable premature weeks of gestation are similar to singletons. Intrauterine growth restriction and prematurity are therefore the principal issues that drive neonatal mortality and morbidity rates in multiple gestations. These data are important for obstetric decision-making and patient counseling. [ABSTRACT FROM AUTHOR]

While electronic fetal heart rate monitoring has become a routine part of intrapartum care, abnormal patterns often alarm physicians needlessly. Pulse oximetry can clarify a confusing FHR pattern and may reduce the risk of perinatal complications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: One variable that has the potential to affect the course of labor but has not been evaluated previously is the adequacy of maternal hydration. Typical orders provide for 125 mL of intravenous fluids per hour in patients taking limited oral fluids. Many such patients are clinically dehydrated. Physiologists have shown that increased fluids improve skeletal muscle performance in prolonged exercise. This study was designed to determine whether increased intravenous fluids affect the progress of labor. STUDY DESIGN: Nulliparous women with uncomplicated singleton gestations at term, in spontaneous active labor with dilatation between 2 and 5 cm, and with a cephalic presentation were included. Patients who gave consent were randomly selected to receive either 125 mL or 250 mL of intravenous fluids per hour. RESULTS: One hundred ninety-five patients were randomly selected, 94 to the 125-mL group and 101 to the 250-mL group. Prerandomization variables were well matched between the 2 groups. The mean volume of total intravenous fluids was significantly greater in the 250-mL group (2008 mL vs 2487 mL; P =.002), as was the mean hourly rate (152 mL/h in the 125-mL group vs 254 mL/h in the 250-mL group; P =.001). The frequency of labor lasting >12 hours was statistically higher in the 125-mL group (20/78 [26%] vs 12/91 [13%]; P =.047). In addition, there was a trend favoring longer mean duration of the first stage and total duration of labor in patients delivered vaginally in the 125-mL group, by 70 and 68 minutes, respectively (P =.06). There was a trend toward a lower frequency of oxytocin administration for inadequate labor progress in the higher fluid rate group (61 [65%] in the 125-mL group vs 51 [49%] in the 250-mL group; P =.06). Cesarean deliveries were more frequent in the 125-mL group (n = 16) than in the 250-mL group (n = 10) but did not reach statistical significance. CONCLUSION: This study presents the novel finding that increasing fluid administration for nulliparous women in labor above rates commonly used is associated with a lower frequency of prolonged labor and possibly less need for oxytocin. Thus inadequate hydration in labor may be a factor contributing to dysfunctional labor and possibly cesarean delivery. Consideration of this factor in clinical management and in future studies considering variables that affect labor is warranted. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Previous studies using repetitive courses of antenatal corticosteroids (ACS) have demonstrated marginal or no benefit and concern over potential risk. No prior prospective or randomized studies have evaluated the option of a single rescue course of ACS on neonatal outcome. STUDY DESIGN: A multicenter randomized double-blind placebo-controlled trial was performed from May 2003 through February 2008 in 18 private (15) and university (3) medical centers. Patients with singletons or twins < 33 weeks who had completed a single course of ACS before 30 weeks and at least 14 days before inclusion, and were judged to have a recurring threat of preterm delivery in the coming week, were included. Patients were randomized to receive a single rescue course of betamethasone, 2 12-mg doses 24 hours apart, or placebo. Exclusion criteria included: premature rupture of membranes, advanced dilation (> 5 cm), chorioamnionitis, and other steroid use. RESULTS: In all, 437 patients were randomized (223 rescue steroid group and 214 placebo group). A total of 55% of patients in each group delivered at < 34 weeks. There was a significant reduction in the primary outcome of composite neonatal morbidity < 34 weeks in the rescue steroid group vs placebo (43.9% vs 63.6%; odds ratio, 0.45; 95% confidence interval, 0.27-0.75; P = .002) and significantly decreased respiratory distress syndrome, ventilator support, and surfactant use. Perinatal mortality and other morbidities were similar in each group. Including all neonates in the analysis (regardless of gestational age at delivery) still demonstrated a significant reduction in composite morbidity in the rescue course group (32.1% vs 42.6%, odds ratio, 0.65; 95% confidence interval, 0.44-0.97; P = .0034) and improvement in respiratory morbidities. CONCLUSION: Administration of a single rescue course of ACS before 33 weeks improves neonatal outcome without apparent increased short-term risk. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of failure to progress, the most common indication for intrapartum cesarean delivery, is based on the assessment of cervical dilation and station over time. Labor curves serve as references for expected changes in dilation and fetal descent. The labor curves of Friedman, Zhang et al, and others are based on time alone and derived from mothers with spontaneous labor onset. However, labor induction is now common, and clinicians also consider other factors when assessing labor progress. Labor curves that consider the use of labor induction and other factors that influence labor progress have the potential to be more accurate and closer to clinical decision-making., Objective: This study aimed to compare the prediction errors of labor curves based on a single factor (time) or multiple clinically relevant factors using two modeling methods: mixed-effects regression, a standard statistical method, and Gaussian processes, a machine learning method., Study Design: This was a longitudinal cohort study of changes in dilation and station based on data from 8022 births in nulliparous women with a live, singleton, vertex-presenting fetus ≥35 weeks of gestation with a vaginal delivery. New labor curves of dilation and station were generated with 10-fold cross-validation. External validation was performed using a geographically independent group. Model variables included time from the first examination in the 20 hours before delivery; dilation, effacement, and station recorded at the previous examination; cumulative contraction counts; and use of epidural anesthesia and labor induction. To assess model accuracy, differences between each model's predicted value and its corresponding observed value were calculated. These prediction errors were summarized using mean absolute error and root mean squared error statistics., Results: Dilation curves based on multiple parameters were more accurate than those derived from time alone. The mean absolute error of the multifactor methods was better (lower) than those of the single-factor methods (0.826 cm [95% confidence interval, 0.820-0.832] for the multifactor machine learning and 0.893 cm [95% confidence interval, 0.885-0.901] for the multifactor mixed-effects method and 2.122 cm [95% confidence interval, 2.108-2.136] for the single-factor methods; P<.0001 for both comparisons). The root mean squared errors of the multifactor methods were also better (lower) than those of the single-factor methods (1.126 cm [95% confidence interval, 1.118-1.133] for the machine learning [P<.0001] and 1.172 cm [95% confidence interval, 1.164-1.181] for the mixed-effects methods and 2.504 cm [95% confidence interval, 2.487-2.521] for the single-factor [P<.0001 for both comparisons]). The multifactor machine learning dilation models showed small but statistically significant improvements in accuracy compared to the mixed-effects regression models (P<.0001). The multifactor machine learning method produced a curve of descent with a mean absolute error of 0.512 cm (95% confidence interval, 0.509-0.515) and a root mean squared error of 0.660 cm (95% confidence interval, 0.655-0.666). External validation using independent data produced similar findings., Conclusion: Cervical dilation models based on multiple clinically relevant parameters showed improved (lower) prediction errors compared to models based on time alone. The mean prediction errors were reduced by more than 50%. A more accurate assessment of departure from expected dilation and station may help clinicians optimize intrapartum management., (Published by Elsevier Inc.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Preterm birth remains the leading cause of morbidity and mortality among nonanomalous neonates in the United States. Unfortunately, preterm birth rates remain high despite current medical interventions such as progestogen supplementation and cerclage placement. Case management, which encompasses coordinated care aimed at providing a more comprehensive and supportive environment, is a key component in improving health and reducing costs in other areas of medicine. However, it has not made its way into the general lexicon and practice of obstetrical care. Case management intended for decreasing prematurity or ameliorating its consequences may include specialty clinics, social services, coordination of specialty services such as nutrition counseling, home visits or frequent phone calls by specially trained personnel, and other elements described herein. It is not currently included in nor is it advocated for as a recommended prematurity prevention approach in the American College of Obstetricians and Gynecologists or Society for Maternal-Fetal Medicine guidelines for medically indicated or spontaneous preterm birth prevention. Our review of existing evidence finds consistent reductions or trends toward reductions in preterm birth with case management, particularly among individuals with high a priori risk of preterm birth across systematic reviews, metaanalyses, and randomized controlled studies. These findings suggest that case management has substantial potential to improve the environmental, behavioral, social, and psychological factors with patients at risk of preterm birth., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rates of labor induction are increasing, raising concerns related to increased healthcare utilization costs. High-dose intravenous fluid (250 cc/h) has been previously demonstrated to shorten the time to delivery in nulliparous individuals in spontaneous labor. Whether or not this relationship exists among individuals undergoing induction of labor is unknown., Objective: Our study aimed to evaluate the effect of high-dose intravenous hydration on time to delivery among nulliparous individuals undergoing induction of labor., Study Design: Nulliparous individuals presenting for induction of labor with a Bishop score of ≤6 (with and without rupture of membranes) were randomized to receive either 125 cc/h or 250 cc/h of normal saline. The primary outcome was length of labor (defined as time from initiation of study fluids to delivery). Both time to overall delivery and vaginal delivery were evaluated. Secondary outcomes included the lengths of each stage of labor, the percentage of individuals delivering within 24 hours, and maternal and neonatal outcomes, including cesarean delivery rate., Results: A total of 180 individuals meeting inclusion criteria were enrolled and randomized. Baseline demographic characteristics were similar between groups; however, there was a higher incidence of diabetes mellitus in the group receiving 125 cc/h. Average length of labor was similar between groups (27.6 hours in 250 cc/h and 27.8 hours in 125 cc/h), as was the length of each stage of labor. Cox regression analysis did not demonstrate an effect of fluid rate on time to delivery. Neither the admission Bishop score, body mass index, nor other demographic characteristics affected time to delivery or vaginal delivery. There were no differences in maternal or neonatal outcomes, including overall cesarean delivery rate, clinically apparent iatrogenic intraamniotic infection, Apgar scores, need for neonatal phototherapy, or neonatal intensive care unit stay., Conclusion: There were no observed differences in the length of labor or maternal or neonatal outcomes with the administration of an increased rate of intravenous fluids among nulliparous individuals undergoing induction of labor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The clinical management of pregnancy and spontaneous preterm birth (sPTB) relies on estimates of gestational age (GA). Our objective was to evaluate the effect of GA dating uncertainty on the observed performance of a validated proteomic biomarker risk predictor, and then to test the generalizability of that effect in a broader range of GA at blood draw. In a secondary analysis of a prospective clinical trial (PAPR; NCT01371019), we compared two GA dating categories: both ultrasound and dating by last menstrual period (LMP) (all subjects) and excluding dating by LMP (excluding LMP). The risk predictor's performance was observed at the validated risk predictor threshold both in weeks 19 1/7 -20 6/7 and extended to weeks 18 0/7 -20 6/7 . Strict blinding and independent statistical analyses were employed. The validated biomarker risk predictor showed greater observed sensitivity of 88% at 75% specificity (increases of 17% and 1%) in more reliably dated (excluding-LMP) subjects, relative to all subjects. Excluding dating by LMP significantly improved the sensitivity in weeks 19 1/7 -20 6/7 . In the broader blood draw window, the previously validated risk predictor threshold significantly stratified higher and lower risk of sPTB, and the risk predictor again showed significantly greater observed sensitivity in excluding-LMP subjects. These findings have implications for testing the performance of models aimed at predicting PTB.

Objectives: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment., Methods: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort ( N  = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p  < .05)., Results: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% ( p  = .029) and 8.5% ( p  = .001), respectively; neonatal costs' point estimate by 16% ( p  = .098); and moderate-to-severe neonatal morbidity/mortality by 29% ( p  = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity., Conclusions: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.

Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of -1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB ( p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan-Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth ( p < 001, p = 0.0016) and rate of hospital discharge for both neonate ( p < 0.001, p = 0.005) and mother ( p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 ( p = 0.0083,) and 7.4-fold higher ( p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes.

Objective: Respiratory distress syndrome (RDS) is implicated in 30% of neonatal deaths. Since prostaglandins promote surfactant secretion and labor is associated with a lower risk of RDS in term neonates, it is plausible that synthetic prostaglandin (sPG) exposure is associated with a lower risk of RDS. Thus, we evaluated the association between sPG exposure and RDS in neonates born after the induction of labor (IOL)., Study Design: Secondary analysis of women with singleton pregnancies undergoing IOL at 34 0/7 to 42 0/7 weeks in the nuMoM2b study, a multicenter prospective cohort of nulliparous women. RDS rates and secondary neonatal outcomes in neonates with intrapartum sPG exposure were compared with those who had IOL with non-sPG methods (e.g., balloon catheter, amniotomy, oxytocin, and laminaria). Logistic regression models estimated the association of sPG with RDS and with secondary outcomes after adjustment for clinical and demographic factors (including gestational age). A sensitivity analysis was performed in which analysis was restricted to those with an admission cervical dilation ≤2 cm., Results: Of 10,038 women in the total cohort, 3,071 met inclusion criteria; 1,444 were exposed and 1,627 were unexposed to sPGs. Antenatal corticosteroid exposure rates were low (3.0%) and similar between groups. In univariable analysis, neonates with sPG exposure had higher rates of RDS (3.2 vs. 2.0%, odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.01-2.50). This relationship was similar by gestational age at delivery (term vs. preterm, interaction p  = 0.14). After adjustment, the association between sPG and RDS was no longer significant (adjusted odds ratio: 1.4, 95% CI: 0.9-2.3). When analysis was restricted to subjects with admission cervical dilation of ≤2 cm, there was also no association between sPG exposure and RDS., Conclusion: In pregnancies between 34 and 42 weeks of gestation, exposure to sPG for cervical ripening or labor induction was not associated with newborn RDS., Key Points: · RDS is implicated in 30% of neonatal deaths.. · sPG exposure was not associated with RDS.. · Avoiding preterm birth remains crucial in RDS prevention.., Competing Interests: None declared., (Thieme. All rights reserved.)

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 95.6–99.2; specificity 99.9 CI 99.6–99.9). 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.

Background: A large recent study analyzed the relationship between multiple factors and neonatal outcome and in preterm births. Study variables included the reason for admission, indication for delivery, optimal steroid use, gestational age, and other potential prognostic factors. Using stepwise multivariable analysis, the only two variables independently associated with serious neonatal morbidity were gestational age and the presence of suspected intrauterine growth restriction as a reason for admission. This finding was surprising given the beneficial effects of antenatal steroids and hazards associated with some causes of preterm birth. Multivariable logistic regression techniques have limitations. Without testing for multiple interactions, linear regression will identify only individual factors with the strongest independent relationship to the outcome for the entire study group. There may not be a single "best set" of risk factors or one set that applies equally well to all subgroups. In contrast, machine learning techniques find the most predictive groupings of factors based on their frequency and strength of association, with no attempt to identify independence and no assumptions about linear relationships. Objective: To determine if machine learning techniques would identify specific clusters of conditions with different probability estimates for severe neonatal morbidity and to compare these findings to those based on the original multivariable analysis. Materials and methods: This was a secondary analysis of data collected in a multicenter, prospective study on all admissions to the neonatal intensive care unit between 2013 and 2015 in 10 hospitals. We included all patients with a singleton, stillborn, or live newborns, with a gestational age between 23 0/7 and 31 6/7 week. The composite endpoint, severe neonatal morbidity, defined by the presence of any of five outcomes: death, grade 3 or 4 intraventricular hemorrhage (IVH), and ≥28 days on ventilator, periventricular leukomalacia (PVL), or stage III necrotizing enterocolitis (NEC), was present in 238 of the 1039 study patients. We studied five explanatory variables: maternal age, parity, gestational age, admission reason, and status with respect to antenatal steroid administration. We concentrated on Classification and Regression Trees because the resulting structure defines clusters of risk factors that often bear resemblance to clinical reasoning. Model performance was measured using area under the receiver-operator characteristic curves (AUC) based on 10 repetitions of 10-fold cross-validation. Results: A hybrid technique using a combination of logistic regression and Classification and Regression Trees had a mean cross-validated AUC of 0.853. A selected point on its receiver-operator characteristic (ROC) curve corresponding to a sensitivity of 81% was associated with a specificity of 76%. Rather than a single curve representing the general relationship between gestational age and severe morbidity, this technique found seven clusters with distinct curves. Abnormal fetal testing as a reason for admission with or without growth restriction and incomplete steroid administration would place a 20-year-old patient on the highest risk curve. Conclusions: Using a relatively small database and a few simple factors known before birth it is possible to produce a more tailored estimate of the risk for severe neonatal morbidity on which clinicians can superimpose their medical judgment, experience, and intuition.

Background: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors., Methods and Findings: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes., Conclusions: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RJW provided expertise on a legal case for LabCorp for which he received compensation. The case was not related to the topic being presented. He is PI for several studies that CUMC receives grants for including support from commercial entities Natera, Inc.; Sequenom; Illumina, Inc. He does not receive compensation from any of these grants.

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.

There is a general consensus that the cesarean delivery rate in the United States is too high, and that practice patterns of obstetricians are largely to blame for this situation. In reality, the US cesarean delivery rate is the result of 3 forces largely beyond the control of the practicing clinician: patient expectations and misconceptions regarding the safety of labor, the medical-legal system, and limitations in technology. Efforts to "do something" about the cesarean delivery rate by promulgating practice directives that are marginally evidence-based or influenced by social pressures are both ineffective and potentially harmful. We examine both the recent American Congress of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine Care Consensus Statement "Safe Prevention of Primary Cesarean Delivery" document and the various iterations of the ACOG guidelines for vaginal birth after cesarean delivery in this context. Adherence to arbitrary time limits for active phase or second-stage arrest without incorporating other clinical factors into the decision-making process is unwise. In a similar manner, ever-changing practice standards for vaginal birth after cesarean driven by factors other than changing data are unlikely to be effective in lowering the cesarean delivery rate. Whether too high or too low, the current US cesarean delivery rate is the expected result of the unique demographic, geographic, and social forces driving it and is unlikely to change significantly given the limitations of current technology to otherwise satisfy the demands of these forces., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest: The authors, except for Dr. Das, are employees of MedNax, Inc., which owns and manages Obstetrix/Pediatrix Medical Group, which funded the study. Dr. Das is a consulting statistician. There are no other conflict of interest.

Background: Prolonged labor has been demonstrated to increase adverse maternal and neonatal outcome. A practice that may decrease the risk of prolonged labor is the modification of fluid intake during labor., Objective: Several studies demonstrated that increased hydration in labor as well as addition of dextrose-containing fluids may be associated with a decrease in length of labor. The purpose of our study was to characterize whether high-dose intravenous fluids, standard-dose fluids with dextrose, or high-dose fluids with dextrose show a difference in the duration of labor in nulliparas., Study Design: Nulliparous subjects with singletons who presented in active labor were randomized to 1 of 3 groups of intravenous fluids: 250 mL/h of normal saline, 125 mL/h of 5% dextrose in normal saline, or 250 mL/h of 2.5% dextrose in normal saline. The primary outcome was total length of labor from initiation of intravenous fluid in vaginally delivered subjects. Secondary outcomes included cesarean delivery rate and length of second stage of labor, among other maternal and neonatal outcomes., Results: In all, 274 subjects who met inclusion criteria were enrolled. There were no differences in baseline characteristics among the 3 groups. There was no difference in the primary outcome of total length of labor in vaginally delivered subjects among the 3 groups. First stage of labor duration, second stage of labor duration, and cesarean delivery rates were also equivalent. There were no differences identified in other secondary outcomes including clinical chorioamnionitis, postpartum hemorrhage, blood loss, Apgar scores, or neonatal intensive care admission., Conclusion: There is no difference in length of labor or delivery outcomes when comparing high-dose intravenous fluids, addition of dextrose, or use of high-dose intravenous fluids with dextrose in nulliparous women who present in active labor., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective  To determine whether exposure to any antenatal corticosteroids is associated with a lower rate of death at each gestational age at which administration is currently recommended. Design  Prospective cohort study. Settings  300 participating neonatal intensive care units of the Pediatrix Medical Group in the United States. Participants  117 941 infants 23 0/7 to 34 6/7 weeks' gestational age born between 1 January 2009 and 31 December 2013. Exposure  Any antenatal corticosteroids. Main outcomes measures  Death or major hospital morbidities analyzed by gestational age and exposure to antenatal corticosteroids with models adjusted for birth weight, sex, mode of delivery, and multiple births. Results  Infants exposed to antenatal corticosteroids (n=81 832) had a significantly lower rate of death before discharge at each gestation 29 weeks or less, 31 weeks, and 33-34 weeks compared with infants without exposure (range of adjusted odds ratios 0.32 to 0.55). The number needed to treat with antenatal corticosteroids to prevent one death before discharge increased from six at 23 and 24 weeks' gestation to 798 at 34 weeks' gestation. The rate of survival without major hospital morbidity was higher among infants exposed to antenatal corticosteroids at the lowest gestations. Infants exposed to antenatal corticosteroids had lower rates of severe intracranial hemorrhage or death, necrotizing enterocolitis stage 2 or above or death, and severe retinopathy of prematurity or death compared with infants without exposure at all gestations less than 30 weeks and most gestations for infants born at 30 weeks' gestation or later. Conclusion  Among infants born from 23 to 34 weeks' gestation, antenatal exposure to corticosteroids compared with no exposure was associated with lower mortality and morbidity at most gestations. The effect size of exposure to antenatal corticosteroids on mortality seems to be larger in infants born at the lowest gestations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Despite intensive efforts directed at initial training in fetal heart rate interpretation, continuing medical education, board certification/recertification, team training, and the development of specific protocols for the management of abnormal fetal heart rate patterns, the goals of consistently preventing hypoxia-induced fetal metabolic acidemia and neurologic injury remain elusive., Objective: The purpose of this study was to validate a recently published algorithm for the management of category II fetal heart rate tracings, to examine reasons for the birth of infants with significant metabolic acidemia despite the use of electronic fetal heart rate monitoring, and to examine critically the limits of electronic fetal heart rate monitoring in the prevention of neonatal metabolic acidemia., Study Design: The potential performance of electronic fetal heart rate monitoring under ideal circumstances was evaluated in an outcomes-blinded examination fetal heart rate tracing of infants with metabolic acidemia at birth (base deficit, >12) and matched control infants (base deficit, <8) under the following conditions: (1) expert primary interpretation, (2) use of a published algorithm that was developed and endorsed by a large group of national experts, (3) assumption of a 30-minute period of evaluation for noncritical category II fetal heart rate tracings, followed by delivery within 30 minutes, (4) evaluation without the need to provide patient care simultaneously, and (5) comparison of results under these circumstances with those achieved in actual clinical practice., Results: During the study period, 120 infants were identified with an arterial cord blood base deficit of >12 mM/L. Matched control infants were not demographically different from subjects. In actual practice, operative intervention on the basis of an abnormal fetal heart rate tracings occurred in 36 of 120 fetuses (30.0%) with metabolic acidemia. Based on expert, algorithm-assisted reviews, 55 of 120 patients with acidemia (45.8%) were judged to need operative intervention for abnormal fetal heart rate tracings. This difference was significant (P=.016). In infants who were born with a base deficit of >12 mM/L in which blinded, algorithm-assisted expert review indicated the need for operative delivery, the decision for delivery would have been made an average of 131 minutes before the actual delivery. The rate of expert intervention for fetal heart rate concerns in the nonacidemic control group (22/120; 18.3%) was similar to the actual intervention rate (23/120; 19.2%; P=1.0) Expert review did not mandate earlier delivery in 65 of 120 patients with metabolic acidemia. The primary features of these 65 cases included the occurrence of sentinel events with prolonged deceleration just before delivery, the rapid deterioration of nonemergent category II fetal heart rate tracings before realistic time frames for recognition and intervention, and the failure of recognized fetal heart rate patterns such as variability to identify metabolic acidemia., Conclusions: Expert, algorithm-assisted fetal heart rate interpretation has the potential to improve standard clinical performance by facilitating significantly earlier recognition of some tracings that are associated with metabolic acidemia without increasing the rate of operative intervention. However, this improvement is modest. Of infants who are born with metabolic acidemia, only approximately one-half potentially could be identified and have delivery expedited even under ideal circumstances, which are probably not realistic in current US practice. This represents the limits of electronic fetal heart rate monitoring performance. Additional technologies will be necessary if the goal of the prevention of neonatal metabolic acidemia is to be realized., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Vasa previa is a rare condition that is associated with a high rate of fetal or neonatal death when not diagnosed antenatally. The majority of available studies are either small, do not include antepartum data, limited to single institutions, or are biased by inclusion of patients from registries and online vasa previa support groups., Objective: The purpose of this study was to investigate the diagnostic and management strategies for this potentially catastrophic entity and to describe further maternal and placental risk factors that may aid in the establishment of a screening protocol for vasa previa., Study Design: This was a retrospective multicenter descriptive study that included all pregnancies that were complicated by vasa previa that delivered between January 1, 2000, and December 31, 2012. Nine maternal fetal medicine practices and the hospitals in which they practice participated in data collection of diagnosis, treatment, and maternal-neonatal outcomes., Results: Sixty-eight pregnancies were identified that included the diagnosis of vasa previa or "possible vasa previa" either in the ultrasound record or in the hospital record at the time of delivery. Four cases (5.8%) appeared to resolve on repeat ultrasound examination. Fifteen of the 64 cases that were suspected of having vasa previa could not be verified or were not documented at delivery. Of the remaining 49 cases, where vasa previa was documented, 47 cases (96%) were diagnosed by ultrasound scanning antenatally. Known risk factors for vasa previa were present in 41 of 47 cases (87%). Of the 49 cases, 41 were delivered by planned cesarean delivery at a mean gestational age of 34.7 weeks, and 8 cases required emergent cesarean delivery at a mean gestational age of 34.6 weeks (range, 32.4-36.0 weeks gestation). Seven of these emergent cesarean deliveries had been diagnosed previously; 1 case had not. All of the emergent cesarean deliveries were for vaginal bleeding; 1 case was also for a concerning fetal heart rate, but only 1 of the known cases had a documented ruptured fetal vessel. None of these cases were found to have cervical shortening before the onset of bleeding. One of the undiagnosed cases resulted in a ruptured fetal vessel and a baby with no heart beat at birth who survived but had periventricular leukomalacia at 1 month of age with mild white-matter atrophy. Of the remaining neonates in this group, there were no deaths and no major complications beyond mild respiratory distress syndrome in 9 cases. There were no other major neonatal complications, which included no cases of periventricular leukomalacia, neonatal sepsis, necrotizing enterocolitis, or any grade of intraventricular hemorrhage in the confirmed cases of vasa previa., Conclusion: This study confirms most current recommendations that include risk-based ultrasound screening, early hospitalization at 30-34 weeks gestation, antenatal corticosteroids at 30-32 weeks gestation, and elective delivery at 33-34 weeks gestation. Thus, with these recommendations for current identification and management of vasa previa in this series of geographically diverse mostly private practice maternal fetal medicine practices, we have confirmed recent reports that show a dramatic improvement in neonatal survival and complications compared with earlier reports., (Copyright © 2016 Elsevier Inc. All rights reserved.)