Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. Registration: NCT05172024.

Tranexamic Acid to Prevent Obstetrical Hemorrhage after Cesarean Delivery.

BACKGROUND: Prophylactic use of tranexamic acid at the time of cesarean delivery has been shown to decrease the calculated blood loss, but the effect on the need for blood transfusions is unclear. METHODS: We randomly assigned patients undergoing cesarean delivery at 31 U.S. hospitals to receive either tranexamic acid or placebo after umbilical-cord clamping. The primary outcome was a composite of maternal death or blood transfusion by hospital discharge or 7 days post partum, whichever came first. Key secondary outcomes were estimated intraoperative blood loss of more than 1 liter (prespecified as a major secondary outcome), interventions for bleeding and related complications, the preoperative-to-postoperative change in the hemoglobin level, and postpartum infectious complications. Adverse events were assessed. RESULTS: A total of 11,000 participants underwent randomization (5529 to the tranexamic acid group and 5471 to the placebo group); scheduled cesarean delivery accounted for 50.1% and 49.2% of the deliveries in the respective groups. A primary-outcome event occurred in 201 of 5525 participants (3.6%) in the tranexamic acid group and in 233 of 5470 (4.3%) in the placebo group (adjusted relative risk, 0.89; 95.26% confidence interval [CI], 0.74 to 1.07; P = 0.19). Estimated intraoperative blood loss of more than 1 liter occurred in 7.3% of the participants in the tranexamic acid group and in 8.0% of those in the placebo group (relative risk, 0.91; 95% CI, 0.79 to 1.05). Interventions for bleeding complications occurred in 16.1% of the participants in the tranexamic acid group and in 18.0% of those in the placebo group (relative risk, 0.90; 95% CI, 0.82 to 0.97); the change in the hemoglobin level was -1.8 g per deciliter and -1.9 g per deciliter, respectively (mean difference, -0.1 g per deciliter; 95% CI, -0.2 to -0.1); and postpartum infectious complications occurred in 3.2% and 2.5% of the participants, respectively (relative risk, 1.28; 95% CI, 1.02 to 1.61). The frequencies of thromboembolic events and other adverse events were similar in the two groups. CONCLUSIONS: Prophylactic use of tranexamic acid during cesarean delivery did not lead to a significantly lower risk of a composite outcome of maternal death or blood transfusion than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT03364491.).

Differential Gene Expression in Cord Blood of Infants Diagnosed with Cerebral Palsy: A Pilot Analysis of the Beneficial Effects of Antenatal Magnesium Cohort.

The Beneficial Effects of Antenatal Magnesium clinical trial was conducted between 1997 and 2007, and demonstrated a significant reduction in cerebral palsy (CP) in preterm infants who were exposed to peripartum magnesium sulfate (MgSO4). However, the mechanism by which MgSO4 confers neuroprotection remains incompletely understood. Cord blood samples from this study were interrogated during an era when next-generation sequencing was not widely accessible and few gene expression differences or biomarkers were identified between treatment groups. Our goal was to use bulk RNA deep sequencing to identify differentially expressed genes comparing the following four groups: newborns who ultimately developed CP treated with MgSO4 or placebo, and controls (newborns who ultimately did not develop CP) treated with MgSO4 or placebo. Those who died after birth were excluded. We found that MgSO4 upregulated expression of SCN5A only in the control group, with no change in gene expression in cord blood of newborns who ultimately developed CP. Regardless of MgSO4 exposure, expression of NPBWR1 and FTO was upregulated in cord blood of newborns who ultimately developed CP compared with controls. These data support that MgSO4 may not exert its neuroprotective effect through changes in gene expression. Moreover, NPBWR1 and FTO may be useful as biomarkers and may suggest new mechanistic pathways to pursue in understanding the pathogenesis of CP. The small number of cases ultimately available for this secondary analysis, with male predominance and mild CP phenotype, is a limitation of the study. In addition, differentially expressed genes were not validated by qRT-PCR.

Maternal Diabetes and Intrapartum Fetal Electrocardiogram.

OBJECTIVE: Fetal electrocardiogram (ECG) ST changes are associated with fetal cardiac hypoxia. Our objective was to evaluate ST changes by maternal diabetic status and stage of labor. METHODS: This was a secondary analysis of a multicentered randomized-controlled trial in which laboring patients with singleton gestations underwent fetal ECG scalp electrode placement and were randomly assigned to masked or unmasked ST-segment readings. Our primary outcome was the frequency of fetal ECG tracings with ST changes by the stage of labor. ECG tracings were categorized into mutually exclusive groups (ST depression, ST elevation without ST depression, or no ST changes). We compared participants with DM, gestational diabetes mellitus (GDM), and no DM. RESULTS: Of the 5,436 eligible individuals in the first stage of labor (95 with pregestational DM and 370 with GDM), 4,427 progressed to the second stage. ST depression occurred more frequently in the first stage of labor in participants with pregestational DM (15%, adjusted odds ratio [aOR] 2.20, 95% confidence interval [CI] 1.14-4.24) and with GDM (9.5%, aOR 1.51, 95% CI 1.02-2.25) as compared with participants without DM (5.7%). The frequency of ST elevation was similar in participants with pregestational DM (33%, aOR 0.79, 95% CI 0.48-1.30) and GDM (33.2%, aOR 0.91, 95% CI 0.71-1.17) as compared with those without DM (34.2%). In the second stage, ST depression did not occur in participants with pregestational DM (0%) and occurred more frequently in participants with GDM (3.5%, aOR 2.01, 95% CI 1.02-3.98) as compared with those without DM (2.0%). ST elevation occurred more frequently in participants with pregestational DM (30%, aOR 1.81, 95% CI 1.02-3.22) but not with GDM (19.0%, aOR 1.06, 95% CI 0.77-1.47) as compared with those without DM (17.8%). CONCLUSION: ST changes in fetal ECG occur more frequently in fetuses of diabetic mothers during labor. CLINICALTRIALS: gov number, NCT01131260. PRECIS: ST changes in fetal ECG, a marker of fetal cardiac hypoxia, occur more frequently in fetuses of diabetic parturients. KEY POINTS: · Fetal hypertrophic cardiomyopathy (HCM) and cardiac dysfunction occur frequently among fetuses of diabetic patients.. · Fetal ECG changes such as ST elevation and depression reflect cardiac hypoxia.. · Fetuses of diabetic patients demonstrate a higher prevalence of fetal ECG tracings with ST changes..

Intrapartum Fetal Electrocardiogram in Small- and Large-for-Gestational Age Fetuses.

OBJECTIVE: This study aimed to evaluate whether intrapartum fetal electrocardiogram (ECG) tracings with ST-elevation or depression occur more frequently in each stage of labor in small-for-gestational age (SGA) or large-for-gestational age (LGA), as compared with appropriate-for-gestational age (AGA) fetuses. STUDY DESIGN: We conducted a secondary analysis of a large, multicenter trial in which laboring patients underwent fetal ECG waveform-analysis. We excluded participants with diabetes mellitus and major fetal anomalies. Birth weight was categorized as SGA (<10th percentile), LGA (>90th percentile), or AGA (10-90th percentile) by using a gender and race/ethnicity specific nomogram. In adjusted analyses, the frequency of ECG tracings with ST-depression or ST-elevation without depression was compared according to birthweight categories and labor stage. RESULTS: Our study included 4,971 laboring patients in the first stage and 4,074 in the second stage. During the first stage of labor, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (6.7 vs. 5.5%; adjusted odds ratio [aOR]: 1.41, 95% confidence interval [CI]: 0.93-2.13), or in ST-elevation without depression (35.8 vs. 34.1%; aOR: 1.17, 95% CI: 0.94-1.46). During the second stage, there were no differences in the frequency of ST-depression in SGA fetuses compared with AGA fetuses (1.6 vs. 2.0%; aOR: 0.69, 95% CI: 0.27-1.73), or in ST-elevation without depression (16.2 vs. 18.1%; aOR: 0.90, 95% CI: 0.67-1.22). During the first stage of labor, there were no differences in the frequency of ST-depression in LGA fetuses compared with AGA fetuses (6.3 vs. 5.5%; aOR: 0.97, 95% CI: 0.60-1.57), or in ST-elevation without depression (33.1 vs. 34.1%; aOR: 0.80, 95% CI: 0.62-1.03); during the second stage of labor, the frequency of ST-depression in LGA compared with AGA fetuses (2.5 vs. 2.0%, aOR: 1.36, 95% CI: 0.61-3.03), and in ST-elevation without depression (15.5 vs. 18.1%; aOR: 0.83, 95% CI: 0.58-1.18) were similar as well. CONCLUSION: The frequency of intrapartum fetal ECG tracings with ST-events is similar among SGA, AGA, and LGA fetuses. KEY POINTS: · SGA and LGA neonates are at increased risk of cardiac dysfunction.. · Fetal ECG has been used to evaluate fetal response to hypoxia.. · Fetal ST-elevation and ST-depression occur during hypoxia.. · Frequency of intrapartum ST-events is similar among SGA, AGA and LGA fetuses..

Intrapartum Resuscitation Interventions for Category II Fetal Heart Rate Tracings and Improvement to Category I.

OBJECTIVE: To evaluate intrapartum resuscitation interventions and improvement in category II fetal heart rate (FHR) tracings. METHODS: This secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis included all participants with category II FHR tracings undergoing intrauterine resuscitation: maternal oxygen, intravenous fluid bolus, amnioinfusion, or tocolytic administration. Fetal heart rate pattern-recognition software was used to confirm category II FHR tracings 30 minutes before intervention and to analyze the subsequent 60 minutes. The primary outcome was improvement to category I within 60 minutes. Secondary outcomes included FHR tracing improvement to category I 30-60 minutes after the intervention and composite neonatal outcome. RESULTS: Of 11,108 randomized participants, 2,251 (20.3%) had at least one qualifying intervention for category II FHR tracings: 63.7% improved to category I within 60 minutes and 50.5% improved at 30-60 minutes. Only 3.4% underwent cesarean delivery and 4.1% an operative vaginal delivery for nonreassuring fetal status within 60 minutes after the intervention. Oxygen administration was the most common intervention (75.4%). Among American College of Obstetricians and Gynecologists-defined subgroups that received oxygen, the absent FHR accelerations and absent-minimal FHR variability subgroup (n=332) was more likely to convert to category I within 60 minutes than the FHR accelerations or "moderate FHR variability" subgroup (n=1,919) (77.0% vs 63.0%, odds ratio [OR] 2.0, 95% CI 1.4-2.7). The incidence of composite neonatal adverse outcome for category II tracings was 2.9% (95% CI 2.2-3.7%) overall; 2.8% (95% CI 2.0-3.8%) for improvement to category I within 60 minutes (n=1,433); and 3.2% (95% CI 2.1-4.6%) for no improvement within 60 minutes (n=818). However, the group with improvement had 29% lower odds for higher level neonatal care (11.8% vs 15.9%, OR 0.71, 95% CI 0.55-0.91). CONCLUSION: Nearly two thirds of category II FHR tracings improved to category I within 60 minutes of intervention with a relatively low overall rate of the composite neonatal adverse outcome. FUNDING SOURCE: Funded in part by Neoventa Medical.

Intrapartum Fetal Heart Rate Tracing Among Small-for-Gestational Age Compared With Appropriate-for-Gestational-Age Neonates.

OBJECTIVE: To compare fetal heart rate (FHR) patterns during the last hour of labor between small-for-gestational-age (SGA; birth weight less than the 10th percentile for gestational age) and appropriate-for-gestational-age (AGA; birth weight at the 10-90th percentile) neonates at 36 weeks of gestation or greater. We also compared the rate of cesarean delivery and composite neonatal morbidity among SGA and AGA newborns. METHODS: This is a secondary analysis of a randomized trial of intrapartum fetal electrocardiographic ST-segment analysis. We excluded women with chorioamnionitis, insufficient duration of FHR tracing in the hour before delivery, and anomalous newborns. Fetal heart rate patterns were categorized by computerized pattern recognition software (PeriCALM Patterns). Composite neonatal morbidity was defined as any of the following: intrapartum fetal death, Apgar score 3 or less at 5 minutes, cord artery pH 7.05 or less, base deficit 12 mmol/L or greater, neonatal seizure, intubation at delivery, neonatal encephalopathy, and neonatal death. Logistic regression was used to evaluate the association between FHR patterns and SGA adjusted for magnesium sulfate exposure and stage of labor. RESULTS: Of the 11,108 women randomized, 85% (n=9,402) met inclusion criteria, of whom 9% were SGA. In the last hour, the likelihood of accelerations was significantly lower among SGA than AGA neonates (72.4% vs 66.8%; P=.001). Variable decelerations lasting greater than 60 seconds, with depth greater than 60 beats per minute (bpm) or nadir less than 60 bpm, were significantly more common with SGA than AGA (all P<.001). The rate of late decelerations, prolonged decelerations, or bradycardia were similar between SGA and AGA (all P>.05). Cesarean delivery for fetal indications was significantly more common with SGA (7.0%) than AGA (4.0%; P<.001). The composite neonatal morbidity was 1.4% among SGA and 1.0% among AGA (odds ratio 1.40, 95% CI 0.74-2.64). CONCLUSION: Although the FHR patterns in the last hour of labor differ among SGA and AGA neonates, as does the rate of cesarean delivery, the composite neonatal morbidity was similar.

Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.

OBJECTIVE: To evaluate the association of magnesium sulfate (MgSO4) exposure and candidate gene polymorphisms with adverse neurodevelopmental outcomes following preterm birth. STUDY DESIGN: We performed a nested case-control analysis of a randomized trial of maternal MgSO4 before anticipated preterm birth for the prevention of cerebral palsy (CP). Cases were children who died within 1 year of life or were survivors with abnormal neurodevelopment at age 2 years. Controls were race- and sex-matched survivors with normal neurodevelopment. We analyzed 45 candidate gene polymorphisms in inflammation, coagulation, and vascular regulation pathways and their association with (1) psychomotor delay, (2) mental delay, (3) CP, and (4) combined outcome of death/CP. Logistic regression analyses, conditional on maternal race and child sex, and adjusted for treatment group, gestational age at birth and maternal education, were performed. RESULTS: Four hundred and six subjects, 211 cases and 195 controls, were analyzed. The strongest association was for IL6R (rs 4601580) in which each additional copy of the minor allele was associated with an increased risk of psychomotor delay (adjusted odds ratio 3.3; 95% confidence interval, 1.7-6.5; p < 0.001). CONCLUSION: Candidate gene polymorphisms are associated with death and adverse neurodevelopmental outcomes following preterm birth. MgSO4 may abrogate this genotype association for some loci.

Association of Cervical Effacement With the Rate of Cervical Change in Labor Among Nulliparous Women.

OBJECTIVE: To assess the association of cervical effacement with the rate of intrapartum cervical change among nulliparous women. METHODS: We conducted a secondary analysis of a prospective trial of intrapartum fetal pulse oximetry. For women who had vaginal deliveries, interval-censored regression was used to estimate the time to dilate at 1-cm intervals. For each given centimeter of progressive cervical dilation, women were divided into those who had achieved 100% cervical effacement and those who had not. The analysis was performed separately for women in spontaneous labor and those who were given oxytocin. RESULTS: A total of 3,902 women were included in this analysis, 1,466 (38%) who underwent labor induction, 1,948 (50%) who underwent labor augmentation (combined for the analysis), and 488 (13%) who labored spontaneously. For women in spontaneous labor, the time to dilate 1 cm was shorter for those who were 100% effaced starting at 4 cm of cervical dilation (P=.01 to <.001). For women who received oxytocin, the time to dilate 1 cm was shorter for those who were 100% effaced throughout labor (P<.001). CONCLUSION: The rate of cervical dilation among nulliparous women is associated with not only the degree of cervical dilation, but also with cervical effacement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00098709.

Antenatal Magnesium and Cerebral Palsy in Preterm Infants.

OBJECTIVE: To evaluate the relationship of maternal antenatal magnesium sulfate (MgSO4) with neonatal cranial ultrasound abnormalities and cerebral palsy (CP). STUDY DESIGN: In a randomized trial of MgSO4 or placebo in women at high risk of preterm delivery, up to 3 cranial ultrasounds were obtained in the neonatal period. Images were reviewed by at least 2 pediatric radiologists masked to treatment and other clinical conditions. Diagnoses were predefined for intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly. CP was diagnosed at 2 years of age by standardized neurologic examination. RESULTS: Intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly were all strongly associated with an increased risk of CP. MgSO4 administration did not affect the risk of cranial ultrasound abnormality observed at 35 weeks postmenstrual age or later. However, for the 82% of infants born at <32 weeks gestation, MgSO4 was associated with a reduction in risk of echolucency or echodensity. The reduction in risk for echolucency explained 21% of the effect of MgSO4 on CP (P = .04), and for echodensity explained 20% of the effect (P = .02). CONCLUSIONS: MgSO4 given prior to preterm delivery was associated with decreased risk of developing echodensities and echolucencies at <32 weeks gestation. However, this effect can only partially explain the effect of MgSO4 on CP at 2 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00014989.

Relation between birth weight and weight and height at the age of 2 in children born preterm.

OBJECTIVE: The aim of the study was to evaluate associations between fetal growth and weight at 2 years in infants born preterm using a customized approach for birth weight. STUDY DESIGN: This is a secondary analysis of a multicenter trial that included a 2-year follow-up of children born prematurely. Customized birth weight percentiles were calculated using the Gardosi model for a U.S. population, and the relation between customized percentile and weight and height at 2 years (adjusted for gender using z-score) was determined using regression analysis and by comparing z-scores for children with birth weight <10th versus ≥10th percentile. RESULTS: Weight z-score at 2 years was significantly lower in the <10th than in the ≥10th percentile group (median [interquartile range, IQR]: -0.66 [-1.58, -0.01] vs. -0.23 [-1.05, 0.55]; p < 0.001), and remained after adjusting for maternal education (p < 0.001). A similar relationship was noted for height z-score between groups (median [IQR]: -0.56 [-1.29, 0.19] vs. -0.24 [-0.99, 0.37]; p < 0.001). Positive relationships between customized birth weight percentile and weight and height at 2 years were noted (p < 0.001 for both), but were not strong (R (2) = 0.04 and 0.02, respectively). CONCLUSION: Customized birth weight percentile is a minor determinant of weight at 2 years among children born preterm.

Relationship between fetal station and successful vaginal delivery in nulliparous women.

OBJECTIVE: To study the relationship between fetal station and successful vaginal delivery in nulliparous women. STUDY DESIGN: This was a secondary analysis from a previously reported trial of pulse oximetry. Vaginal delivery rates were evaluated and compared with respect to the fetal station. Spontaneous labor and induction of labor groups were evaluated separately. Multivariable logistic regression analysis was performed to adjust for confounding factors. RESULTS: Successful vaginal delivery was more frequent with an engaged vertex for spontaneous labor (86.2% versus 78.6%; p = 0.01) and induced labor (87.7% versus 66.1%; p < 0.01). After adjustment, engaged fetal vertex was not associated with vaginal delivery for spontaneous labor (odds ratio [OR] 1.5; 95% confidence interval [CI] 0.95 to 2.3; p = 0.08) or for women with induced labor (OR 2.2; 95% CI 0.96 to 5.1; p = 0.06). CONCLUSION: Among nulliparous women enrolled in the FOX randomized trial in spontaneous labor or for labor induction, an engaged fetal vertex does not affect their vaginal delivery rate.

Umbilical cord blood biomarkers of neurologic injury and the risk of cerebral palsy or infant death.

To evaluate the association between cerebral palsy (CP) or infant death and putative cord blood biomarkers of neurologic injury, we performed a nested case-control secondary analysis of a multicenter randomized trial of magnesium sulfate (MgSO(4)) versus placebo to prevent CP or death among offspring of women with anticipated delivery from 24 to 31 weeks' gestation. Cases were infants who died by 1 year (n=25) or developed CP (n=16), and were matched 1:2 to a control group (n=82) that survived without developing CP. Umbilical cord sera concentrations of S100B, neuron-specific enolase (NSE) and the total soluble form of the receptor for advanced glycation end-products (sRAGE) were measured by ELISA in duplicates. Maternal characteristics were similar between the 2 groups. Cases were born at a lower gestational age (GA) and had lower birth weight compared with controls. There were no differences in concentrations of the three biomarkers and the composite outcome of CP or infant death. However, S100B was higher (median 847.3 vs. 495.7 pg/ml; P=0.03) in infants who had CP and total sRAGE was lower (median 1259.3 vs. 1813.1 pg/ml; P=0.02) in those who died compared with the control group. When corrected for delivery GA and treatment group, both differences lost statistical significance. In conclusion, cord blood S100B level may be associated with CP, but this association was not significant after controlling for GA and MgSO(4) treatment.

Failed labor induction: toward an objective diagnosis.

OBJECTIVE: To evaluate maternal and perinatal outcomes in women undergoing labor induction with an unfavorable cervix according to duration of oxytocin administration in the latent phase of labor after ruptured membranes. METHODS: This was a secondary analysis of a randomized multicenter trial in which all cervical examinations from admission were recorded. INCLUSION CRITERIA: nulliparas at or beyond 36 weeks of gestation undergoing induction with a cervix of 2 cm or less dilated and less than completely effaced. The latent phase of labor was defined as ending at a cervical dilation of 4 cm and effacement of at least 90%, or at a cervical dilation of 5 cm regardless of effacement. RESULTS: A total of 1,347 women were analyzed. The overall vaginal delivery rate was 63.2%. Most women had exited the latent phase after 6 hours of oxytocin and membrane rupture (n=939; 69.7%); only 5% remained in the latent phase after 12 hours. The longer the latent phase, the lower the vaginal delivery rate. Even so, 39.4% of the 71 women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Chorioamnionitis, endometritis, or both, and uterine atony were the only maternal adverse outcomes related to latent-phase duration: adjusted odds ratios (95% confidence intervals) of 1.12 (1.07, 1.17) and 1.13 (1.06, 1.19), respectively, for each additional hour. Neonatal outcomes were not related to latent-phase duration. CONCLUSION: Almost 40% of the women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Therefore, it is reasonable to avoid deeming labor induction a failure in the latent phase until oxytocin has been administered for at least 12 hours after membrane rupture. LEVEL OF EVIDENCE: III.

Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes.

OBJECTIVE: The purpose of this study was to assess maternal and perinatal outcomes as a function of second-stage labor duration. STUDY DESIGN: We assessed outcomes in nulliparous laboring women who were enrolled in a trial of fetal pulse oximetry. RESULTS: Of 5341 participants, 4126 women reached the second stage of labor. As the duration of the second stage increased, spontaneous vaginal delivery rates declined, from 85% when the duration was <1 hour to 9% when it was > or =5 hours. Adverse maternal outcomes that were associated significantly with the duration of the second stage of labor included chorioamnionitis (overall rate, 3.9%), third- or fourth-degree perineal laceration (overall rate, 8.7%), and uterine atony (overall rate, 3.9%). Odds ratios for each additional hour of the second stage of labor ranged from 1.3-1.8. Among individual adverse neonatal outcomes, only admission to a neonatal intensive care unit was associated significantly with second stage duration (odds ratio, 1.4). CONCLUSION: The second stage of labor does not need to be terminated for duration alone.

Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.

OBJECTIVE: To review the evidence regarding neuroprotective effects of antenatal exposure to magnesium sulfate. DATA SOURCES: We conducted database searches of MEDLINE, the Cochrane Library and Controlled Trials Register, as well as the ClinicalTrials.gov and International Clinical Trials Register websites. Bibliographies of all relevant articles were reviewed. METHODS OF STUDY SELECTION: Randomized controlled trials comparing magnesium sulfate with placebo/other treatment in patients at risk of preterm delivery were evaluated for inclusion and methodological quality. The primary outcome was death or cerebral palsy by 18-24 months corrected age. Secondary outcomes were death, cerebral palsy, moderate-severe cerebral palsy, and death or moderate-severe cerebral palsy. Separate analyses were performed according to the gestational age (GA) at randomization (less than 32 to 34 weeks and less than 30 weeks) and for studies in which magnesium sulfate was used exclusively for fetal neuroprotection. TABULATION, INTEGRATION, AND RESULTS: Five randomized controlled trials were included (5,235 fetuses/infants). When analyzed by GA at randomization, in utero exposure to magnesium sulfate at less than 32-34 weeks did not reduce the rate of death or cerebral palsy (relative risk [RR] 0.92, 95% confidence interval [CI] 0.83-1.03). However, cerebral palsy (RR 0.70, 95% CI 0.55-0.89), moderate-severe cerebral palsy (RR 0.60, 95% CI 0.43-0.84), and death or moderate-severe cerebral palsy were significantly reduced, without an evident increase in the risk of death (RR 1.01, 95% CI 0.89-1.14). Similar results were obtained when the GA at randomization was less than 30 weeks. When only neuroprotection trials (four trials, 4,324 fetuses/infants) are analyzed, in utero exposure to magnesium sulfate additionally reduced the primary outcome of death or cerebral palsy. The number needed to treat to prevent one case of cerebral palsy among those who survive until age 18-24 months is 46 (95% CI 26-187) in infants exposed to magnesium sulfate in utero before 30 weeks, and 56 (95% CI 34-164) in infants exposed to magnesium sulfate in utero before 32 to 34 weeks. CONCLUSION: Fetal exposure to magnesium sulfate in women at risk of preterm delivery significantly reduces the risk of cerebral palsy without increasing the risk of death.

Maternal obesity, uterine activity, and the risk of spontaneous preterm birth.

OBJECTIVE: To assess the associations among maternal obesity, uterine contraction frequency, and spontaneous preterm birth in women at risk for spontaneous preterm birth. METHODS: In a secondary analysis, we analyzed data from 253 women at risk for spontaneous preterm birth (prior spontaneous preterm birth, vaginal bleeding) enrolled in a multicenter observational study of home uterine activity monitoring at 11 centers. All women wore a uterine activity monitor twice daily from 22 weeks through 34 weeks of gestation. Mean and maximal contractions/hour at 22-24, 25-26, 27-28, 29-30, 31-32 weeks, and at or after 33 weeks of gestation were compared between overweight/obese women (a body mass index [BMI] at 22-24 weeks greater than 25 kg/m) and normal/underweight women (a BMI of 25 kg/m or less) at each gestational age interval. Multivariable analysis evaluated the influences of BMI, contractions, fetal fibronectin, and transvaginal cervical length on spontaneous preterm birth before 35 weeks. RESULTS: Obese/overweight women (n=156) were significantly less likely to experience spontaneous preterm birth before 35 weeks (8.3% compared with 21.7%, P<.01). For each gestational age interval before 32 weeks, obese/overweight women had fewer mean contractions/hour (P<.01 for each) and maximal contractions/hour (P<.01 for each) than normal/underweight women, although their mean cervical lengths (34.3 mm compared with 33.1 mm, P=.25), and fetal fibronectin levels (7.1% compared with 7.2% 50 ng/mL or more, P=.97) were similar at study enrollment. Obese/overweight status was associated with a lower risk of spontaneous preterm birth before 35 weeks after controlling for contraction frequency and other factors evaluated at 22-24 weeks, but not at later periods. CONCLUSION: Obese/overweight women at risk for spontaneous preterm birth exhibit less uterine activity and less frequent spontaneous preterm birth before 35 weeks of gestation than normal/underweight women. LEVEL OF EVIDENCE: II.

Plasma CRH measurement at 16 to 20 weeks' gestation does not predict preterm delivery in women at high-risk for preterm delivery.

OBJECTIVE: The purpose of this study was to examine the utility of a single second-trimester plasma corticotropin-releasing hormone measurement as a marker for preterm delivery in women at high risk for preterm delivery. STUDY DESIGN: This is an analysis of data from a multicenter placebo-controlled trial designed to evaluate the role of 17 alpha hydroxyprogesterone caproate (17P) in the prevention of recurrent preterm birth. Women with a documented history of a previous spontaneous preterm birth at <37 weeks were enrolled (16-20 wks) and randomly assigned in a 2 to 1 ratio to weekly injections of 17P or matching placebo. Blood was collected before treatment in 170 patients (113 assigned 17P and 57 placebo) who were enrolled at 11 of the 19 centers. Plasma levels of corticotropin-releasing hormone were compared between those who delivered preterm and those delivering at term. Data were analyzed using the Wilcoxon rank-sum test. RESULTS: The overall rates of preterm birth in this cohort of 170 patients were 35.9% at <37 weeks (31.9% progesterone, 43.9% placebo), and 19.4% at <35 weeks (18.6% vs 21.1%). The median levels of corticotropin-releasing hormone were similar between those delivering at <37 weeks and those delivering > or = 37 weeks (0.39 ng/mL vs 0.37 ng/mL, P = .08). In addition, there were no differences in corticotropin-releasing hormone levels among those who delivered at <35 weeks or > or = 35 weeks (0.36 vs 0.38, P = .90). Moreover, there were no differences in corticotropin-releasing hormone levels among those in the placebo group who delivered at <37 or > or = 37 weeks (0.40 vs 0.41, P = .72) and at <35 or > or = 35 weeks (P = .64). CONCLUSION: A single measurement of corticotropin-releasing hormone at 16 to 20 weeks' gestation is not a good biomarker for recurrent preterm delivery in patients at high risk for this complication.

Complications of anesthesia for cesarean delivery.

OBJECTIVE: To quantify anesthesia-related complications associated with cesarean delivery in a well-described, prospectively ascertained cohort from multiple university-based hospitals in the United States and to evaluate whether certain factors would identify women at increased risk for a failed regional anesthetic. METHODS: A prospective observational study was conducted of women (n = 37,142) with singleton gestations undergoing cesarean delivery in the centers forming the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Detailed information was collected regarding choice of anesthesia and procedure-related complications, including failed regional anesthetic and maternal death. Potential risk factors for a failed regional anesthetic were analyzed. RESULTS: Of the women studied, 34,615 (93%) received a regional anesthetic. Few (3.0%) regional procedures failed, and related maternal morbidity was rare. Increased maternal size, higher preoperative risk, rapid decision-to-incision interval, and placement later in labor were all significantly related to an increased risk of a failed regional procedure. Of the general anesthetics, 38% were administered when the decision-to-incision interval was less than 15 minutes. Women deemed at the greatest preoperative risk (American Society of Anesthesiologists score > or = 4) were approximately 7-fold more likely to receive a general anesthetic (odds ratio 6.9, 95% confidence interval 5.83-8.07). There was one maternal death, due to a failed intubation, in which the anesthetic procedure was directly implicated. CONCLUSION: Regional techniques have become the preferred method of anesthesia for cesarean delivery. Procedure-related complications are rare and attest to the safety of modern obstetric anesthesia for cesarean delivery in the United States.