Prediction and Prevention of Preterm Birth: A Prospective, Randomized Intervention Trial.

OBJECTIVE: The study aimed to determine if a program of mid-trimester serum proteomics screening of women at low risk for spontaneous preterm birth (sPTB) and the use of a PTB risk-reduction protocol in those whose results indicated an increased risk of sPTB would reduce the likelihood of sPTB and its sequelae. STUDY DESIGN: Prospective comparison of birth outcomes in singleton pregnancies with mid-trimester cervical length ≥2.5 cm and at otherwise low risk for sPTB randomized to undergo or not undergo mid-trimester serum proteomics screening for increased risk of sPTB (NCT03530332). Screen-positive women were offered a group of interventions aimed at reducing the risk of spontaneous PTB. The primary outcome was the rate of sPTB <37 weeks, and secondary outcomes were gestational age at delivery, total length of neonatal stay, and NICU length of stay (LOS). Unscreened and screen-negative women received standard care. The adaptive study design targeted a sample size of 3,000 to 10,000 women to detect a reduction in sPTB from 6.4 to 4.7%. Due to limited resources, the trial was stopped early prior to data unblinding. RESULTS: A total of 1,191 women were randomized. Screened and unscreened women were demographically similar. sPTB <37 weeks occurred in 2.7% of screened women and 3.5% of controls (p = 0.41). In the screened compared with the unscreened group, there were no between-group differences in the gestational age at delivery, total length of neonatal stay, and NICU LOS. However, the NICU LOS among infants admitted for sPTB was significantly shorter (median = 6.8 days, interquartile range [IQR]: 1.8-8.0 vs. 45.5 days, IQR: 34.6-79.0; p = 0.005). CONCLUSION: Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB compared with women not screened, though the trial was underpowered thus limiting the interpretation of negative findings. Infants in the screened group had a significantly shorter NICU LOS, a difference likely due to a reduced number of infants in the screened group that delivered <35 weeks. KEY POINTS: · Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB, though the trial was underpowered.. · NICU LOS following sPTB was significantly shortened among women who underwent screening and risk-reduction management.. · The use of serum biomarkers may contribute to a practical strategy to reduce sPTB sequelae..

Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix: The TOPS Randomized Clinical Trial.

Importance: A short cervix as assessed by transvaginal ultrasound is an established risk factor for preterm birth. Study findings for a cervical pessary to prevent preterm delivery in singleton pregnancies with transvaginal ultrasound evidence of a short cervix have been conflicting. Objective: To determine if cervical pessary placement decreases the risk of preterm birth or fetal death prior to 37 weeks among individuals with a short cervix. Design, Setting, and Participants: We performed a multicenter, randomized, unmasked trial comparing a cervical pessary vs usual care from February 2017 through November 5, 2021, at 12 centers in the US. Study participants were nonlaboring individuals with a singleton pregnancy and a transvaginal ultrasound cervical length of 20 mm or less at gestations of 16 weeks 0 days through 23 weeks 6 days. Individuals with a prior spontaneous preterm birth were excluded. Interventions: Participants were randomized 1:1 to receive either a cervical pessary placed by a trained clinician (n = 280) or usual care (n = 264). Use of vaginal progesterone was at the discretion of treating clinicians. Main Outcome and Measures: The primary outcome was delivery or fetal death prior to 37 weeks. Results: A total of 544 participants (64%) of a planned sample size of 850 were enrolled in the study (mean age, 29.5 years [SD, 6 years]). Following the third interim analysis, study recruitment was stopped due to concern for fetal or neonatal/infant death as well as for futility. Baseline characteristics were balanced between participants randomized to pessary and those randomized to usual care; 98.9% received vaginal progesterone. In an as-randomized analysis, the primary outcome occurred in 127 participants (45.5%) randomized to pessary and 127 (45.6%) randomized to usual care (relative risk, 1.00; 95% CI, 0.83-1.20). Fetal or neonatal/infant death occurred in 13.3% of those randomized to receive a pessary and in 6.8% of those randomized to receive usual care (relative risk, 1.94; 95% CI, 1.13-3.32). Conclusions and Relevance: Cervical pessary in nonlaboring individuals with a singleton gestation and with a cervical length of 20 mm or less did not decrease the risk of preterm birth and was associated with a higher rate of fetal or neonatal/infant mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02901626.

Timing of Maternal Discharge after Cesarean Delivery and Risk of Maternal Readmission.

OBJECTIVE: Despite legislation and hospital policies (present in some institutions) mandating a minimum length of stay in an effort to decrease the frequency of hospital readmissions, the effectiveness of this approach remains uncertain.We hypothesized that following cesarean delivery (CD), the rates of maternal readmission or unscheduled health care visits are lower in patients discharged on postoperative day (POD) 3 or ≥4 as compared with those discharged earlier on POD 2. METHODS: This is a secondary analysis of a multicenter randomized trial comparing adjunctive azithromycin for unscheduled CD to prevent infection. Groups were compared based on the duration of hospitalization measured in days from delivery (POD 0) to day of discharge and categorized as POD 2, 3, and ≥4. The primary outcome was the composite of any maternal postpartum readmission, unscheduled clinic, or emergency room (ER) visit, within 6 weeks of delivery. Secondary outcomes included components of the primary outcome and neonatal readmissions. We excluded women with hypertensive disorders of pregnancy and infections diagnosed prior to POD 2. RESULTS: A total of 1,391 patients were included. The rate of the primary outcome of any readmission increased with POD at discharge: 5.9% for POD 2, 9.4% for POD 3, and 10.9% for POD ≥4 group (trend for p = 0.03). The primary outcome increased with later discharge (POD ≥4 when compared with POD 2). Among components of the composite, ER and unscheduled clinic visits, but not maternal readmissions, increased with the timing of discharge for patients discharged on POD ≥4 when compared with POD 2. Using logistic regression, discharge on POD 3 and on POD ≥4 was significantly associated with the composite (adjusted odds ratios [aOR] 2.6, 95% confidence interval [CI] [1.3-5.3]; aOR 2.9, 95% CI [1.3-6.4], respectively) compared with POD 2. CONCLUSION: The risk of maternal readmission composite following uncomplicated but unscheduled CD was not lower in patients discharged home on POD 3 or ≥4 compared with patients discharged earlier (POD 2). KEY POINTS: · Risk of maternal readmission is higher in patients discharged on POD 3 or 4 compared with POD 2.. · No significant differences by the timing of discharge were observed for any neonatal readmissions.. · Timing of discharge should include an individualized approach with the option of discharge by POD 2..

Evaluation of an external fetal electrocardiogram monitoring system: a randomized controlled trial.

OBJECTIVE: The objective of the study was to compare interpretability of 2 intrapartum abdominal fetal heart rate-monitoring strategies. We hypothesized that an external fetal electrocardiography monitoring system, a newer technology using wireless abdominal pads, would generate more interpretable fetal heart rate data compared with standard external Doppler fetal heart rate monitoring (standard external monitoring). STUDY DESIGN: We conducted a randomized controlled trial at 4 Utah hospitals. Patients were enrolled at labor admission and randomized in blocks based on body mass index to fetal electrocardiography or standard external monitoring. Two reviewers, blinded to study allocation, reviewed each fetal heart rate tracing. The primary outcome was the percentage of interpretable minutes of fetal heart rate tracing. An interpretable minute was defined as >25% fetal heart rate data present and no more than 25% continuous missing fetal heart rate data or artifact present. Secondary outcomes included the percentage of interpretable minutes of fetal heart rate tracing obtained while on study device only, the number of device adjustments required intrapartum, clinical outcomes, and patient/provider device satisfaction. We determined that 100 patients per arm (200 total) would be needed to detect a 5% difference in interpretability with 95% power. RESULTS: A total of 218 women were randomized, 108 to fetal electrocardiography and 110 to standard external monitoring. Device setup failure occurred more often in the fetal electrocardiography group (7.5% [8 of 107] vs 0% [0 of 109] for standard external monitoring). There were no differences in the percentage of interpretable tracing between the 2 groups. However, fetal electrocardiography produced more interpretable fetal heart rate tracing in subjects with a body mass index ≥30 kg/m2. When considering the percentage of interpretable minutes of fetal heart rate tracing while on study device only, fetal electrocardiography outperformed standard external monitoring for all subjects, regardless of maternal body mass index. Maternal demographics and clinical outcomes were similar between arms. In the fetal electrocardiography group, more device changes occurred compared with standard external monitoring (51% vs 39%), but there were fewer nursing device adjustments (2.9 vs 6.2 mean adjustments intrapartum, P < .01). There were no differences in physician device satisfaction scores between groups, but fetal electrocardiography generated higher patient satisfaction scores. CONCLUSION: Fetal electrocardiography performed similarly to standard external monitoring when considering percentage of interpretable tracing generated in labor. Furthermore, patients reported overall greater satisfaction with fetal electrocardiography in labor. Fetal electrocardiography may be particularly useful in patients with a body mass index ≥30 kg/m2.

Risks of cause-specific mortality in offspring of pregnancies complicated by hypertensive disease of pregnancy.

BACKGROUND: Fetal environment has a substantial influence on an individual's health throughout their life course. Animal models of hypertensive disease of pregnancy have demonstrated adverse health outcomes among offspring exposed to hypertensive disease of pregnancy in utero. Although there are numerous descriptions of the neonatal, infant, and pediatric outcomes of human offspring affected by hypertensive disease of pregnancy, there are few data in US populations on later life outcomes, including mortality. OBJECTIVE: To assess risk for early mortality among offspring of pregnancies complicated by hypertensive disease of pregnancy. STUDY DESIGN: This is a retrospective cohort study of offspring born to women with singleton or twin pregnancies between 1947 and 1967 with birth certificate information in the Utah Population Database. We identified offspring from delivery diagnoses of gestational hypertension, preeclampsia, or eclampsia. Offspring from these pregnancies (exposed) were matched to offspring of pregnancies without hypertensive disease of pregnancy (unexposed) by maternal age at delivery, birth year, sex, and multiple gestation. We also identified unexposed siblings of exposed offspring for a separate sibling analysis. Mortality follow-up of all offspring continued through 2016, at which time they would have been 49-69 years old. Adjusted hazard ratios for cause-specific mortality comparing exposed with unexposed offspring were estimated using Cox proportional hazard models. RESULTS: We compared mortality risks for 4050 exposed offspring and 6989 matched unexposed offspring from the general population and 7496 unexposed siblings. Mortality risks due to metabolic, respiratory, digestive, nervous, and external causes of death did not differ between exposed and unexposed groups. Mortality risks from cardiovascular disease were greater in exposed offspring compared with unexposed offspring (adjusted hazard ratio, 1.57; 95% confidence interval, 1.16-2.12). In sex-specific models among the general population, cardiovascular disease mortality was significantly associated with exposure among male patients (adjusted hazard ratio, 1.92; 95% confidence interval, 1.27-2.88) but not among female patients (adjusted hazard ratio, 0.97; 95% confidence interval, 0.81-1.94). An interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality was significant (P=.047), suggesting that the effect of hypertensive disease of pregnancy on cardiovascular disease mortality increased with higher birth order. Among siblings, the association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality was not significant (adjusted hazard ratio, 1.39; 95% confidence interval, 0.99-1.95), and this was also true for sex-specific analyses of males (adjusted hazard ratio, 1.26; 95% confidence interval, 0.81-1.94) and females (adjusted hazard ratio, 1.71; 95% confidence interval, 0.96-3.04). As in the general population, there was a significant interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality (P=.011). CONCLUSION: In a US population, overall mortality risks are greater for offspring of pregnancies complicated by hypertensive disease of pregnancy compared with unexposed offspring. Among siblings, there was not a significant association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality.

Cervicovaginal fluid proteomic analysis to identify potential biomarkers for preterm birth.

BACKGROUND: Spontaneous preterm birth is a leading cause of neonatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could reduce the spontaneous preterm birth rate, but conventional methods such as obstetrical history and maternal cervical length screening identify only a minority of spontaneous preterm birth cases. Cervicovaginal fluid might prove to be a useful, readily available biological fluid for identifying spontaneous preterm birth biomarkers. OBJECTIVE: The objective of the study was to identify cervicovaginal fluid biomarkers of early spontaneous preterm birth in a high-risk cohort of pregnant women with a history of spontaneous preterm birth using targeted and shotgun proteomic analyses. STUDY DESIGN: A nested case control study (cases were spontaneous preterm birth <34 weeks in the current pregnancy; controls were spontaneous labor and delivery at 39-41 weeks) was performed using cervicovaginal fluid samples collected at 3 study visits (100/7 to 186/7 weeks, 190/7 to 236/7 weeks, and 280/7 to 316/7 weeks). All participants had a history of at least 1 prior spontaneous preterm birth. Targeted proteomic analysis was performed using a stable isotope-labeled proteome derived from endocervical and vaginal mucosal cells. This served as a standard to quantitate candidate protein levels in individual cervicovaginal fluid samples from the second and third study visits using liquid chromatography-multiple reaction monitoring mass spectrometry. The ratio of endogenous peptide area/stable isotope-labeled proteome-derived peptide area was used to measure levels of 42 peptides in 22 proteins. To maximize biomarker discovery in the cervicovaginal fluid samples, shotgun proteomic analysis also was performed utilizing liquid chromatography and ion trap mass spectrometry. A validation study was performed in second-trimester cervicovaginal fluid samples from an independent study group (12 spontaneous preterm birth cases, 19 term delivery controls) using enzyme-linked immunosorbent assay for 5 proteins expressed at higher levels in spontaneous preterm birth cases compared with controls in targeted or shotgun proteomic analyses. RESULTS: For targeted proteomics, cervicovaginal fluid samples from 33 cases and 32 controls at 190/7 to 236/7 weeks and 16 cases and 14 controls at 280/7 to 316/7 weeks from the same pregnancies were analyzed. When samples were compared between cases and controls, the relative abundance of 5 proteins was greater (P = .02-.05) in cases at both visits, while the relative abundance of 1 protein was lower (P = .03) in cases at both visits. For shotgun proteomics analyses, cervicovaginal fluid samples were pooled for 9 spontaneous preterm birth cases and 9 term delivery controls at each study visit. Shotgun proteomics yielded 28 proteins that were detected at levels >2 times higher and 1 protein that was detected at a level <0.5 times lower in spontaneous preterm birth cases compared with controls at all 3 study visits. Validation enzyme-linked immunosorbent assay for 5 proteins that were detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases compared with term delivery controls in proteomics analyses did not demonstrate statistically significant differences between spontaneous preterm birth cases and controls. CONCLUSIONS: Potential biomarkers of spontaneous preterm birth were identified by targeted and shotgun proteomics analyses in cervicovaginal fluid samples from high-risk, asymptomatic women. Many of the proteins detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases are extracellular matrix proteins and/or regulate cell membrane physiology. These proteins have substantial biological interest, but validation enzyme-linked immunosorbent assay for 5 of these proteins did not yield clinically useful biomarkers for spontaneous preterm birth.

The Goal of Continuous Fetal Heart Rate Monitoring During Labor: Have We Been Successful?

Despite its ubiquitous use, fetal heart rate (FHR) monitoring has not resulted in a significant reduction in hypoxic-ischemic encephalopathy following delivery. This manuscript reviews the reasons for this failure including limitations of FHR to accurately predict hypoxia, low prevalence of hypoxic-ischemic encephalopathy, and lack of standardization of interpretation and intervention. We propose an alternative goal for FHR monitoring during labor to provide optimal care by early identification of truly concerning features, initiation of appropriate interventions, clear documentation of concerns and plans, and clear communication between team members on labor and delivery, including initiation of the chain of command as needed.

Identification of the Fetus at Risk for Metabolic Acidemia Using Continuous Fetal Heart Rate Monitoring.

The fetal heart rate can be used to assess the current metabolic state of the fetus and predict the risk of the evolution of metabolic acidemia through the course of labor. In this chapter, we will present the pathophysiology of the development of fetal acidemia and provide an organized approach to identifying the risk of worsening acidemia using changes noted in the fetal heart rate pattern to allow for interventions that might alter this course.

The Golden Hours of Fetal Heart Rate Monitoring: Systematic Approach to the Critical Times of Labor and Delivery.

The first hour after admission and the last hour before delivery are critical times for identifying and preventing hypoxic-ischemic encephalopathy. These are times of transition that require coordinated steps to identify fetuses at risk, institute effective plans for fetal heart rate monitoring, and to establish situational awareness. Interpretation and intervention based on fetal heart rate monitoring is an important part of the care provided during these crucial times. We present checklists for the first and last hour of labor for use on labor and delivery to help standardize and optimize the approach to care during these times.

Management of the Category II Fetal Heart Rate Tracing.

Management of the category II fetal heart rate (FHR) tracing presents a common challenge in obstetrics. Up to 80% of women will have a category II FHR tracing at some point during labor. Here we propose a management algorithm to identify specific features of the FHR tracing that correlate with risk for fetal acidemia, target interventions to address FHR decelerations, and guide clinicians about when to proceed toward operative vaginal delivery or cesarean to achieve delivery before there is a high risk for significant fetal acidemia with potential for neurological injury or death.

Long-term mortality risk and life expectancy following recurrent hypertensive disease of pregnancy.

BACKGROUND: Women with a history of hypertensive disease of pregnancy have increased risks for early mortality from multiple causes. The effect of recurrent hypertensive disease of pregnancy on mortality risk and life expectancy is unknown. OBJECTIVE: We sought to determine whether recurrent hypertensive disease of pregnancy is associated with increased mortality risks. STUDY DESIGN: In this retrospective cohort study, we used birth certificate data to determine the number of pregnancies affected by hypertensive disease of pregnancy for each woman delivering in Utah from 1939 through 2012. We assigned women to 1 of 3 groups based on number of affected pregnancies: 0, 1, or ≥2. Exposed women had ≥1 affected singleton pregnancy and lived in Utah for ≥1 year postpartum. Exposed women were matched 1:2 to unexposed women by age, year of childbirth, and parity. Underlying cause of death was determined from death certificates. Mortality risks by underlying cause of death were compared between exposed and unexposed women as a function of number of affected pregnancies. Cox regressions controlled for infant sex, gestational age, parental education, ethnicity, and marital status. RESULTS: We identified 57,384 women with ≥1 affected pregnancy (49,598 women with 1 affected pregnancy and 7786 women with ≥2 affected pregnancies). These women were matched to 114,768 unexposed women. As of 2016, 11,894 women were deceased: 4722 (8.2%) exposed and 7172 (6.3%) unexposed. Women with ≥2 affected pregnancies had increased mortality from all causes (adjusted hazard ratio, 2.04; 95% confidence interval, 1.76-2.36), diabetes (adjusted hazard ratio, 4.33; 95% confidence interval, 2.21-8.47), ischemic heart disease (adjusted hazard ratio, 3.30; 95% confidence interval, 2.02-5.40), and stroke (adjusted hazard ratio, 5.10; 95% confidence interval, 2.62-9.92). For women whose index pregnancy delivered from 1939 through 1959 (n = 10,488), those with ≥2 affected pregnancies had shorter additional life expectancies than mothers who had only 1 or 0 hypertensive pregnancies (48.92 vs 51.91 vs 55.48 years, respectively). CONCLUSION: Hypertensive diseases of pregnancy are associated with excess risks for early all-cause mortality and some cause-specific mortality, and these risks increase further with recurrent disease.

Anticipatory Corticosteroid Administration to Asymptomatic Women with a Short Cervix.

OBJECTIVE: A short cervix is an important risk factor for spontaneous preterm birth. There is substantial evidence that antenatal exposure to corticosteroids significantly benefits infants that are born when delivery occurs between 24 and 34 weeks' gestation and after 48 hours but within 7 days of their administration. Our study was to evaluate whether asymptomatic women who are given a course of antenatal corticosteroids (ACS) at the time a short cervix is identified deliver within the window of proven steroid benefit. STUDY DESIGN: This was a retrospective chart review of patients who had a cervical length of < 2.5 cm between 23 and 34 weeks and who did not have cervical dilation or significant symptoms of preterm labor. RESULTS: Of 367 asymptomatic patients with a short cervix, only two (0.5%) delivered within 7 days of the time a short cervix was identified. With a policy of giving ACS at the time an ultrasound shows a short cervix, 184 patients would have to be treated for each one who realizes a steroid benefit by delivering within 7 days. CONCLUSION: We conclude that unless future studies show that neonates benefit from ACS given more than 7 days before delivery, giving ACS to asymptomatic women solely because the cervix is short is not advised.

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women.

BACKGROUND: Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. OBJECTIVE: We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. STUDY DESIGN: Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days' and 22 weeks 6 days' gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. RESULTS: Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. CONCLUSION: In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies.

Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women.

Importance: Spontaneous preterm birth is a leading cause of infant mortality. Prediction, largely based on prior pregnancy outcomes, is not possible in women pregnant for the first time. Objective: To assess the accuracy of universal screening to predict spontaneous preterm birth in nulliparous women using serial measurements of vaginal fetal fibronectin levels and cervical length. Design, Settings, and Participants: A prospective observational cohort study of nulliparous women with singleton pregnancies, from 8 clinical sites across the United States between October 2010 and May 2014. Women and clinicians were blinded to results unless cervical shortening less than 15 mm was identified. Exposures: Transvaginal cervical length and quantitative vaginal fetal fibronectin levels were reviewed at 2 study visits 4 or more weeks apart. Main Outcomes and Measures: Spontaneous preterm birth at less than 37 weeks was the primary outcome. Cervical length and quantitative fetal fibronectin were considered independently and together at each visit. Measurement distributions were compared for spontaneous preterm birth vs all other births. Spontaneous preterm birth before 32 weeks was a secondary outcome. Results: The study included 9410 women (median age, 27.0 [interquartile range, 9.0] years; 60.7% non-Hispanic white, 13.8% non-Hispanic black, 16.5% Hispanic, 4.0% Asian, and 5.1% other), of whom 474 (5.0%) had spontaneous preterm births, 335 (3.6%) had medically indicated preterm births, and 8601 (91.4%) had term births. Among women with spontaneous preterm birth, cervical length of 25 mm or less occurred in 35 of 439 (8.0%) at 16 to 22 weeks' gestation and in 94 of 403 (23.3%) at 22 to 30 weeks' gestation. Fetal fibronectin levels of 50 ng/mL or greater at 16 to 22 weeks identified 30 of 410 women (7.3%) with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to 30 weeks. The area under the receiver operating characteristic curve for screening between 22 and 30 weeks for fetal fibronectin level alone was 0.59 (95% CI, 0.56-0.62), for transvaginal cervical length alone was 0.67 (95% CI, 0.64-0.70), and for the combination as continuous variables was 0.67 (95% CI, 0.64-0.70). Conclusions and Relevance: Among nulliparous women with singleton pregnancies, quantitative vaginal fetal fibronectin and serial transvaginal ultrasound cervical length had low predictive accuracy for spontaneous preterm birth. These findings do not support routine use of these tests in such women.

Detection and confirmation of serum lipid biomarkers for preeclampsia using direct infusion mass spectrometry.

Despite substantial research, the early diagnosis of preeclampsia remains elusive. Lipids are now recognized to be involved in regulation and pathophysiology of some disease. Shotgun lipidomic studies were undertaken to determine whether serum lipid biomarkers exist that predict preeclampsia later in the same in pregnancy. A discovery study was performed using sera collected at 12-14 weeks pregnancy from 27 controls with uncomplicated pregnancies and 29 cases that later developed preeclampsia. Lipids were extracted and analyzed by direct infusion into a TOF mass spectrometer. MS signals, demonstrating apparent differences were selected, their abundances determined, and statistical differences tested. Statistically significant lipid markers were reevaluated in a second confirmatory study having 43 controls and 37 preeclampsia cases. Multi-marker combinations were developed using those lipid biomarkers confirmed in the second study. The initial study detected 45 potential preeclampsia markers. Of these, 23 markers continued to be statistically significant in the second confirmatory set. Most of these markers, representing several lipid classes, were chemically characterized, typically providing lipid class and potential molecular components using MS(2) Several multi-marker panels with areas under the curve >0.85 and high predictive values were developed. Developed panels of serum lipidomic biomarkers appear to be able to identify most women at risk for preeclampsia in a given pregnancy at 12-14 weeks gestation.

A genome-wide association study of early spontaneous preterm delivery.

Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple-testing adjustments. We analyzed DNA samples from mother-infant pairs from early SPTB cases (20(0/7)-33(6/7) weeks, 959 women and 979 neonates) and term delivery controls (39(0/7)-41(6/7) weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P-values between 10×10(-5) and 10×10(-6). The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P-value of 1.0×10(-6). Two neonatal SNPs reached the genome-wide significance threshold, including rs17527054 on chromosome 6p22 with a P-value of 2.7×10(-12) and rs3777722 on chromosome 6q27 with a P-value of 1.4×10(-10). However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome-wide case-control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB.

Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system.

BACKGROUND: Spontaneous preterm birth remains a leading cause of neonatal morbidity and mortality among nonanomalous neonates in the United States. Spontaneous preterm birth tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent spontaneous preterm birth. Unfortunately, one-third of high-risk women will have a recurrent spontaneous preterm birth despite 17-alpha hydroxyprogesterone caproate therapy; the reasons for this variability in response are unknown. OBJECTIVE: We hypothesized that clinical factors among women treated with 17-alpha hydroxyprogesterone caproate who suffer recurrent spontaneous preterm birth at a similar gestational age differ from women who deliver later, and that these associations could be used to generate a clinical scoring system to predict 17-alpha hydroxyprogesterone caproate response. STUDY DESIGN: Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth <37 weeks' gestation. Participants received daily omega-3 supplementation or placebo for the prevention of recurrent preterm birth; all were provided 17-alpha hydroxyprogesterone caproate. Women were classified as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest previous spontaneous preterm birth. Responders were women with pregnancy extending ≥3 weeks later compared with the delivery gestational age of their earliest previous preterm birth; nonresponders delivered earlier or within 3 weeks of the gestational age of their earliest previous preterm birth. A risk score for nonresponse to 17-alpha hydroxyprogesterone caproate was generated from regression models via the use of clinical predictors and was validated in an independent population. Data were analyzed with multivariable logistic regression. RESULTS: A total of 754 women met inclusion criteria; 159 (21%) were nonresponders. Responders delivered later on average (37.7±2.5 weeks) than nonresponders (31.5±5.3 weeks), P<.001. Among responders, 27% had a recurrent spontaneous preterm birth (vs 100% of nonresponders). Demographic characteristics were similar between responders and nonresponders. In a multivariable logistic regression model, independent risk factors for nonresponse to 17-alpha hydroxyprogesterone caproate were each additional week of gestation of the earliest previous preterm birth (odds ratio, 1.23; 95% confidence interval, 1.17-1.30, P<.001), placental abruption or significant vaginal bleeding (odds ratio, 5.60; 95% confidence interval, 2.46-12.71, P<.001), gonorrhea and/or chlamydia in the current pregnancy (odds ratio, 3.59; 95% confidence interval, 1.36-9.48, P=.010), carriage of a male fetus (odds ratio, 1.51; 95% confidence interval, 1.02-2.24, P=.040), and a penultimate preterm birth (odds ratio, 2.10; 95% confidence interval, 1.03-4.25, P=.041). These clinical factors were used to generate a risk score for nonresponse to 17-alpha hydroxyprogesterone caproate as follows: black +1, male fetus +1, penultimate preterm birth +2, gonorrhea/chlamydia +4, placental abruption +5, earliest previous preterm birth was 32-36 weeks +5. A total risk score >6 was 78% sensitive and 60% specific for predicting nonresponse to 17-alpha hydroxyprogesterone caproate (area under the curve=0.69). This scoring system was validated in an independent population of 287 women; in the validation set, a total risk score >6 performed similarly with a 65% sensitivity, 67% specificity and area under the curve of 0.66. CONCLUSIONS: Several clinical characteristics define women at risk for recurrent preterm birth at a similar gestational age despite 17-alpha hydroxyprogesterone caproate therapy and can be used to generate a clinical risk predictor score. These data should be refined and confirmed in other cohorts, and women at high risk for nonresponse should be targets for novel therapeutic intervention studies.

Global "omics" evaluation of human placental responses to preeclamptic conditions.

BACKGROUND: Preeclampsia (PE) is a leading cause of maternal death. Its cause is still debated but there is general agreement that the placenta plays a central role. Perhaps the most commonly proposed contributors to PE include placental hypoxia, oxidative stress, and increased proinflammatory cytokines. How the placenta responds to these abnormalities has been considered but not as part of a comprehensive analysis of low-molecular-weight biomolecules and their responses to these accepted PE conditions. OBJECTIVE: Using a peptidomic approach, we sought to identify a set of molecules exhibiting differential expression in consequence of provocative agents/chemical mediators of PE applied to healthy human placental tissue. STUDY DESIGN: Known PE conditions were imposed on normal placental tissue from 13 uncomplicated pregnancies and changes in the low-molecular-weight peptidome were evaluated. A t test was used to identify potential markers for each imposed stress. These markers were then submitted to a least absolute shrinkage and selection operator multinomial logistic regression model to identify signatures specific to each stressor. Estimates of model performance on external data were obtained through internal validation. RESULTS: A total of 146 markers were increased/decreased as a consequence of exposure to proposed mediators of PE. Of these 75 changed with hypoxia; 23 with hypoxia-reoxygenation/oxidative stress and 48 from exposure to tumor necrosis factor-α. These markers were chemically characterized using tandem mass spectrometry. Identification rates were: hypoxia, 34%; hypoxia-reoxygenation, 60%; and tumor necrosis factor-α, 50%. Least absolute shrinkage and selection operator modeling specified 16 markers that effectively distinguished all groups, ie, the 3 abnormal conditions and control. Bootstrap estimates of misclassification rates, multiclass area under the curve, and Brier score were 0.108, 0.944, and 0.160, respectively. CONCLUSION: Using this approach we found previously unknown molecular changes in response to individual PE conditions that allowed development biomolecular signatures for exposure to each accepted pathogenic condition.

Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.

BACKGROUND: Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response. OBJECTIVE: We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder." STUDY DESIGN: This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression. RESULTS: One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort. CONCLUSION: Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention.