A Randomized Trial of the Effects of Ambient Operating Room Temperature on Neonatal Morbidity.

OBJECTIVE: Newborn hypothermia has been implicated in neonatal morbidity without randomized evidence that it compromises the infant. Our objective was to determine if a difference in operating room temperature at cesarean birth impacts neonatal morbidity. STUDY DESIGN: Women undergoing cesarean delivery of a liveborn infant without major malformations were included. The institutional preexisting operating room temperature of 20°C (67°F) was compared with an experimental group of 24°C (75°F) by cluster randomization assigned on a weekly basis. Newborn hypothermia was defined as axillary temperature on arrival to the nursery of less than 36.5°C (<97.7°F). The primary outcome was a composite of neonatal morbidity including respiratory support, sepsis, hypoglycemia, and neonatal death. RESULTS: Between November 2016 and May 2018, 5,221 women had cesarean deliveries at Parkland Hospital with 2,817 randomized to the standard care group and 2,404 to the experimental group. The rate of neonatal composite morbidity did not differ between the groups: standard care 398 (14%) versus experimental 378 (16%), p = 0.11. This was despite a significant decrease in the rate of neonatal hypothermia: standard care 1,195 (43%) versus experimental 414 (18%), p < 0.001. There was no difference in the composite outcome for preterm infants (<37 wk) between the groups: standard care 194 (49%) versus experimental 185 (54%), p = 0.25. CONCLUSION: An 8°F increase in operating room temperature was significantly associated with a reduced rate of neonatal hypothermia, although this decrease was not associated with a significant improvement in neonatal morbidity. However, the increase in operating room temperature was met with resistance from obstetricians and operating room personnel. This trial is registered (registration no.: NCT03008577).

Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

OBJECTIVE: To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death. STUDY DESIGN: This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes (n = 11) and demographic and clinical factors (n = 10) evident by the time of discharge among surviving infants (n = 1889) and the primary outcome of death or moderate/severe CP at age 2 (n = 73) was estimated, and a prediction model was created. RESULTS: Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants. CONCLUSION: IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae. KEY POINTS: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..

Tranexamic acid for prevention of hemorrhage in elective repeat cesarean delivery-a randomized study.

BACKGROUND: The American College of Obstetricians and Gynecologists states that the current data are insufficient to recommend tranexamic acid prophylaxis for postpartum hemorrhage. OBJECTIVE: This study's objective was to evaluate if prophylactic tranexamic acid treatment reduces the calculated blood loss when compared with a placebo in women undergoing an elective repeat cesarean delivery. STUDY DESIGN: This was a double-blind, randomized, placebo-controlled trial in which the calculated blood loss was determined after administration of prophylactic doses of 1 g of tranexamic acid before skin incision and after placental delivery and standard uterotonics in women with singleton pregnancies at ≥37 weeks' gestation presenting for their second or third cesarean delivery under neuraxial anesthesia. The primary outcome was calculated blood loss at 24 hours. The calculation was based on each participant's height, weight, and the difference in hematocrit before the start of surgery and 24 hours after delivery. Prespecified secondary outcomes were quantification of maternal coagulation activity during the perioperative course. A sample size of 50 women per group was planned (N=100) based on a meta-analysis of mean reduction in blood loss after tranexamic acid. RESULTS: A total of 723 women were screened, and 110 women were randomized as follows: 55 to the tranexamic acid group and 55 to the placebo group. The primary outcome of mean calculated blood loss was 2274±469 mL for the tranexamic acid group and 2407±388 mL for the placebo group (P>.05). For the secondary outcomes, D-dimer levels were lower in the tranexamic acid group than in the placebo group 24 hours after delivery (2.1±1.2 µg/mL vs 4.3±2.4 µg/mL; P<.001). CONCLUSION: Prophylactic tranexamic acid treatment did not decrease the mean calculated blood loss. Significantly less participants had a calculated blood loss >2000 mL in the tranexamic acid group than in the placebo group and had lower levels of D-dimer at 24 hours.

Episiotomy: Evolution of a Common Obstetric Practice at a Public Hospital.

OBJECTIVE: This study aimed to evaluate the rate and impact of episiotomy on maternal and newborn outcomes before and after restricted use of episiotomy. STUDY DESIGN: This population-based observational study used an obstetric database of all deliveries since 1990 that has been maintained with quality checks. Inclusion criteria were vaginal deliveries at ≥37 weeks. Exclusion criteria included fetal malformations, multifetal gestations, or fetal deaths known on arrival to Labor and Delivery. The primary outcomes of interest were episiotomy, perineal lacerations, and newborn outcomes. To evaluate the impact of restrictive episiotomy, data from 1990 to 1997 (35% overall episiotomy rate) were compared with data from 2010 to 2017 (2.5% overall episiotomy rate). Univariable analysis of maternal and infant outcomes were performed comparing the two-time epochs with the Pearson's Chi-squared test. RESULTS: Overall, 268,415 women met inclusion criteria and 49,089 (18.2%) had an episiotomy. The rate of episiotomy decreased from 37% of deliveries in 1990 to 2% in 2017. A total of 82,082 deliveries occurred in the 1990 to 1997 epoch and 57,183 in 2010 to 2017. Indicated use of episiotomy was associated with a significant decrease in third and fourth degree lacerations. Immediate newborn condition (5-minute Apgar's score ≤3 and umbilical artery pH <7.1) and neonatal outcomes (intraventricular hemorrhage [IVH] grade 3/4, positive culture sepsis, neonatal seizures, and neonatal demise) were not significantly different. CONCLUSION: Selective, indicated use of episiotomy compared with routine was associated with lower rates of third/fourth-degree lacerations with no change in neonatal outcomes. The common obstetric practice of routinely performing episiotomy, presumably to prevent perineal trauma, proved untrue when analyzed over almost three decades. KEY POINTS: · Episiotomy use decreased overtime at our institution.. · Decreased episiotomy use was associated with significant improvement in maternal outcomes.. · Neonatal outcomes were unchanged suggesting no deleterious effects with restricted episiotomy..

Nifedipine for Acute Tocolysis of Preterm Labor: A Placebo-Controlled Randomized Trial.

OBJECTIVE: To evaluate the effectiveness of acute nifedipine tocolysis in preventing preterm birth in women in preterm labor. METHOD: This was a randomized, double-blind, placebo-controlled trial of nifedipine in women with a singleton pregnancy between 28 0/7 and 33 6/7 weeks of gestation who were admitted with uterine activity, intact membranes, and cervical dilatation from 2 to 4 cm. Women were randomized to receive nifedipine 20 mg or placebo orally, followed by a repeat dose after 90 minutes if contractions persisted. The study drug was continued every 4 hours to complete a 48-hour regimen. The primary outcome was birth before 37 weeks of gestation. A total of 150 women were necessary to detect a one-third reduction in this outcome. After treating 88 patients, a preplanned interim analysis of blinded outcomes by the Data Safety Monitoring Committee recommended discontinuation of the trial due to futility. RESULTS: A total of 90 women were enrolled between May 2014 and November 2017. After two women withdrew, 88 were analyzed: 46 in the nifedipine group and 42 in the placebo group. There was no significant difference in the primary outcome of delivery before 37 weeks of gestation in the nifedipine group compared with the placebo group (52% vs 48%, relative risk [RR] 1.1, 95% CI 0.7-1.7), nor in the secondary outcome of delivery at least 48 hours from randomization (78% vs 71%, respectively, RR 1.1, 95% CI 0.9-1.4). There were also no significant differences between groups in neonatal outcomes. CONCLUSION: Acute tocolysis of preterm labor with nifedipine did not affect preterm birth rates, delivery within 48 hours, or neonatal outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02132533.

A chronicle of the 17-alpha hydroxyprogesterone caproate story to prevent recurrent preterm birth.

Preterm birth is a substantial public health concern. In 2019, the US preterm birth rate was 10.23%, which is the fifth straight year of increase in this rate. Moreover, preterm birth accounts for approximately 1 in 6 infant deaths, and surviving children often suffer developmental delay or long-term neurologic impairment. Although the burden of preterm birth is clear, identifying strategies to reduce preterm birth has been challenging. On October 29, 2019, a US Food and Drug Administration advisory committee voted 9 vs 7 to withdraw interim accelerated approval of 17-alpha hydroxyprogesterone caproate for preventing recurrent preterm birth because the called for a confirmatory trial, known as the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial, was not confirmatory. The Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial included subjects enrolled in the United States and Canada to ensure that at least 10% of patients would be from North America; however, this trial took 9 years to complete and did not demonstrate significant treatment effects in the 2 primary outcomes of interest. Delivery before 35 weeks' gestation occurred in 122 of 1130 women (11%) given 17-alpha hydroxyprogesterone caproate compared with 66 of 578 women (11.5%) given placebo (relative risk, 0.95; 95% confidence interval, 0.71-1.26; P=.72). Similarly, the coprimary outcome neonatal composite index occurred in 61 of 1093 women (5.6%) given 17-alpha hydroxyprogesterone caproate compared with 28 of 559 women (5.0%) given placebo (relative risk, 1.12; 95% confidence interval, 0.68-1.61; P=.73). There was also a lack of efficacy for 17-alpha hydroxyprogesterone caproate treatment in the analysis of a variety of secondary outcomes. Like the Maternal-Fetal Medicine Units Network trial, the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial was also flawed. Importantly, the Maternal-Fetal Medicine Unit Network trial was the sole justification for treating women in the United States with 17-alpha hydroxyprogesterone caproate for nearly 2 decades. Currently, despite more than half a century, 17-alpha hydroxyprogesterone caproate still has not been found to be clearly effective. In this context, how does the advising physician dependent on scientific evidence advise a patient that 17-alpha hydroxyprogesterone caproate is effective when the evidence to support this advice has repeatedly been found to be inadequate? This clinical opinion is a critical appraisal of the 2 randomized trials examining the efficacy of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth and a chronicle of events in the regulatory process of drug approval to help answer this question. With this examination, these events illustrate the complexity of pharmaceutical regulations in the era of accelerated Food and Drug Administration approval and characterize the financial impact and influence in medicine. In this report, we also emphasize the value of observational studies in contemporary practice and identify other examples in medicine where accelerated Food and Drug Administration approval has been withdrawn. Importantly, the themes of the 17-alpha hydroxyprogesterone caproate story are not limited to obstetrics. It can also serve as a microcosm of issues within the US healthcare system, which ultimately contributes to the high cost of healthcare. In our opinion, the answer to the question is clear-the facts speak for themselves-and we believe 17-alpha hydroxyprogesterone caproate should not be endorsed for use to prevent recurrent preterm birth in the United States.

Foley Bulb Added to an Oral Misoprostol Induction Protocol: A Cluster Randomized Trial.

OBJECTIVE: To evaluate whether the induction of labor in term gravid women with cervical dilation 2 cm or less and intact membranes by using oral misoprostol preceded by transcervical Foley bulb placement results in a significantly increased vaginal delivery rate compared with the use of oral misoprostol alone. METHODS: We randomized the induction method by week of admission to labor and delivery, with each week group described as a cluster in a block randomized design. Women with gestational age of 37 weeks or greater, cervical dilation 2 cm or less, intact membranes, and indication for labor induction were included. Study arms were either 100 micrograms of oral misoprostol after transcervical Foley bulb placement or 100 micrograms of oral misoprostol alone. The primary outcome was vaginal delivery with the first induction attempt. Secondary outcomes included time to delivery, clinical chorioamnionitis (maternal temperature of 38°C or greater during labor with or without fundal tenderness, without other identified cause), cesarean delivery indication, and adverse outcomes. We estimated that a sample size of 1,077 per arm was needed to detect a 5% increase in vaginal delivery rate with a type I error of 5% and power of 80%, accounting for interim analysis and cluster size of 30 inductions per week. This was a pragmatic trial, and analysis was by intention-to-treat. RESULTS: From January 1, 2018, to May 13, 2019, 1,117 women (34 clusters) were assigned to oral misoprostol plus Foley and 1,110 women (34 clusters) to oral misoprostol alone. Demographic characteristics were similar. Vaginal delivery at the first induction occurred in 78% of the misoprostol plus Foley arm and in 77% of the misoprostol arm (relative risk [RR] 1.00; 95% CI 0.96-1.05; adjusted relative risk [aRR], 1.00; 95% CI 0.95-1.05). Clinical chorioamnionitis occurred in 18% of the misoprostol plus Foley arm and in 14% of the misoprostol arm (RR 1.30; 95% CI 1.07-1.58; aRR 1.30; 95% CI 1.08-1.56). There were no differences in neonatal outcomes. CONCLUSION: Induction of labor in gravid women at term with intact membranes by using oral misoprostol plus Foley bulb did not result in a higher vaginal delivery rate, but it did result in more clinical chorioamnionitis compared with the use of oral misoprostol alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03407625.

Second-stage labor: consensus versus science.

There has been a recent significant evolution in suggested practices for the management of labor because of the increased national cesarean delivery rate. One of the most significant changes was promulgated by the 2014 Obstetric Care Consensus entitled, "Safe Prevention of Primary Cesarean Delivery," which recommended reconsideration of the upper limits of the length of labor in the second stage as well as the first stage. We previously published a 2016 Clinical Opinion challenging the second-stage practice change. Over the past 2 years, there have been at least 5 reports as well as 2 national organization statements supporting revised management of second-stage labor. We now revisit the second-stage issue because we believe that it is important to carefully clarify the current status resulting from consensus statements as well as the evolving current status of scientific evidence. We structured this Clinical Opinion using questions in an effort to chronicle the story of how obstetric precepts on second-stage labor in use for more than 50 years were being replaced. How did we get here? What is the current evidence? What can be learned from this experience? Should American obstetrics now "fall back" to pre-existing obstetric precepts for the management of second-stage labor after having "sprung forward" an additional hour-namely, lengthening the duration of acceptable second-stage labor to 4 hours as recommended by the Obstetric Care Consensus? We believe that the data published since our 2016 Clinical Opinion buttress our original position that prolongation of the second stage beyond historical precepts is unsafe.

"New or not-so-new" labor management practices and cesarean delivery for arrest of progress.

BACKGROUND: Because nearly one-third of births in the United States are now achieved by cesarean delivery, comprising more than 1.27 million women each year, national organizations have recently published revised guidelines for the management of labor. These new guidelines stipulate that labor arrest should not be diagnosed unless ≥6 cm cervical dilatation has been reached or labor has been stimulated for at ≥6 hours. OBJECTIVE: To determine the cervical dilatation and hours of labor stimulation prior to cesarean delivery for arrest of dilatation. MATERIALS AND METHODS: Between January 1, 1999, andDecember 31, 2000, a prospective observational study of all primary cesarean deliveries was conducted at 13 university centers comprising the Eunice Kennedy Shriver National Institute for Child Health and Human Development, Maternal-Fetal Medicine Units Network. This secondary analysis includes all live-born, singleton, nonanomalous, cephalic gestations delivered by primary cesarean delivery at ≥37 weeks. A cesarean delivery was considered to have been performed for arrest of dilatation if the indication for the procedure was failure to progress, cephalopelvic disproportion, or failed induction. Augmentation was defined as stimulation after spontaneous labor had been previously diagnosed. Analysis included both the latent and active phases of labor. The active phase of labor was diagnosed when cervical dilatation was ≥4 cm in the presence of uterine contractions. RESULTS: A total of 13,269 primary cesarean deliveries were available for analysis, 8,546 (65%) of which were performed for inadequate progress of labor with cervical dilatation recorded at the time of cesarean delivery. Of these cesarean deliveries for labor arrest, a total of 719 (8%) were performed in the latent phase of labor and 7827 (92%) were performed when cervical dilatation was ≥4 cm (active phase). Approximately two-thirds (n = =5876; 69%) received intrauterine pressure monitoring. A total of 5636 women (66% of those reaching the active phase of labor) had reached ≥6 cm cervical dilatation before cesarean delivery was performed. Moreover, 7440 (95%) of the 7827 women in active labor had ≥6 cm dilatation or had received labor stimulation ≥6 hours prior to cesarean delivery for arrest of dilatation. CONCLUSION: Women undergoing primary cesarean delivery for arrest of dilatation 15 years before the recommendations of the Obstetrics Care Consensus had received bona fide efforts to achieve adequate labor consistent with the recommendations of the Consensus. Because 95% of these women had ≥6 cm dilatation or had received labor stimulation ≥6 hours prior to cesarean delivery for arrest of dilatation, these new recommendations are unlikely to change the cesarean delivery rates.

Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery.

OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10-4), accounted for linkage disequilibrium between markers. RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10-4) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant. CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.

Duration of Operative Vaginal Delivery and Adverse Obstetric Outcomes.

OBJECTIVE: This study aimed to evaluate whether the number of vacuum pop-offs, the number of forceps pulls, or the duration of operative vaginal delivery (OVD) is associated with adverse maternal and perinatal outcomes. STUDY DESIGN: This is a secondary analysis of a multicenter observational cohort of women who underwent an attempted OVD. Women were stratified by the duration of OVD and the number of pop-offs (vacuum) or pulls (forceps) attempted. Severe perineal lacerations, failed OVD, and a composite adverse neonatal outcome were compared by the duration of OVD and number of pop-offs or pulls. RESULTS: Of the 115,502 women in the primary cohort, 5,325 (4.6%) underwent an attempt at OVD: 3,594 (67.5%) with vacuum and 1,731 (32.5%) with forceps. After adjusting for potential confounders, an increasing number of pop-offs was associated with an increased odds of the composite adverse neonatal outcome. However, an increasing duration of vacuum exhibited a stronger association with the composite adverse neonatal outcome. Similarly, the number of forceps pulls was less strongly associated with the composite adverse neonatal outcome compared with the duration of forceps application. CONCLUSION: The duration of OVD may be more associated with adverse neonatal outcomes than the number of pop-offs or pulls.

Closed Incision Negative Pressure Therapy in Morbidly Obese Women Undergoing Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of incisional negative pressure wound therapy in the prevention of postoperative wound morbidity in women with class III obesity undergoing cesarean delivery. METHODS: In an open label randomized controlled trial, women admitted for delivery with class III obesity (body mass index 40 or higher) measured within 2 weeks of admission for delivery were offered participation in the study. They were consented either in the outpatient maternal-fetal medicine specialty clinic, during admission to labor and delivery and before a decision to perform cesarean delivery, or in the preoperative area of the hospital before scheduled cesarean delivery. Exclusion criteria included anticoagulation therapy, human immunodeficiency virus infection, and silver or acrylic allergy. Those who ultimately underwent cesarean delivery were randomized to standard surgical dressing or incisional negative pressure wound therapy dressing. The primary outcome was wound morbidity. Preplanned secondary outcomes included characteristics of composite wound morbidity, and hospital, emergency room, and clinic utilization. The sample size estimate required randomization of 440 women to detect a 50% decrease in composite outcome. RESULTS: Between January 1, 2015, and July 31, 2016, 850 women were screened and 677 women with class III obesity were enrolled. Of these, 441 underwent cesarean delivery and were subsequently randomized (219 to standard dressing and 222 to incisional negative pressure wound therapy). The primary outcome, overall composite wound morbidity rate, was 18%. This was not different between the two cohorts (incisional negative pressure wound therapy 17% vs standard dressing 19%, relative risk 0.9 [95% CI 0.5-1.4]). CONCLUSION: Prophylactic incisional negative pressure wound therapy use did not reduce postoperative wound morbidity when compared with a standard surgical dressing in women with class III obesity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02289157.

Cord Blood Haptoglobin, Cerebral Palsy and Death in Infants of Women at Risk for Preterm Birth: A Secondary Analysis of a Randomised Controlled Trial.

BACKGROUND: Antenatal exposure to intra-uterine inflammation results in precocious Haptoglobin (Hp) expression (switch-on status). We investigated the relationships between foetal Hp expression at birth with newborn and childhood outcomes. METHODS: We evaluated cord blood samples from 921 newborns of women at imminent risk for preterm delivery randomised to either placebo (n = 471, birth gestational age (GA) median [min-max]: 31 [24-41] weeks) or magnesium sulphate (n = 450, GA 31 [24-42] weeks]). Primary outcome was infant death by 1 year and/or cerebral palsy (CP) ≥ 2 years of corrected age. Adjusted odd ratios (aOR) for neonatal and childhood outcomes were calculated controlling for GA, birth weight, sex, and magnesium exposure. FINDINGS: Primary outcome occurred in 2.8% of offspring. Newborns were classified in three pre-defined categorisation groups by cord blood Hp switch status and IL-6 levels: inflammation-nonexposed (Category 1, n = 432, 47%), inflammation-exposed haptoglobinemic (Category 2, n = 449, 49%), and inflammation-exposed anhaptoglobinemic or hypohaptoglobinemic (Category 3, n = 40, 4%). Newborns, found anhaptoglobinemic or hypohaptoglobinemic (Category 3) had increased OR for intraventricular haemorrhage (IVH) and/or death (aOR: 7.0; 95% CI: 1.4-34.6, p = 0.02) and for CP and/or death (aOR: 6.27; 95% CI: 1.7-23.5, p = 0.006) compared with Category 2. Foetal ability to respond to inflammation by haptoglobinemia resulted in aOR similar to inflammation-nonexposed newborns. Hp1-2 or Hp2-2 phenotypes protected against retinopathy of prematurity (aOR = 0.66; 95% CI 0.48-0.91, p = 0.01). INTERPRETATION: Foetal ability to switch-on Hp expression in response to inflammation was associated with reduction of IVH and/or death, and CP and/or death. Foetuses unable to mount such a response had an increased risk of adverse outcomes.Trial Registration: clinicaltrials.gov Identifier: NCT00014989.

Risk of Ischemic Placental Disease in Relation to Family History of Preeclampsia.

OBJECTIVE: To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). STUDY DESIGN: We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. RESULTS: Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% (n = 5,374) on all three family members, 26.5% (n = 2,562) in mother and sister(s) only, and 11.6% (n = 1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00-1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12-2.13) and 1.35 (95% CI: 1.03-1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. CONCLUSION: This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.

Daytime Compared With Nighttime Differences in Management and Outcomes of Postpartum Hemorrhage.

OBJECTIVE: To assess whether postpartum hemorrhage management or subsequent morbidity differs based on whether delivery occurred during the day or night. METHODS: We conducted a secondary analysis of a multicenter observational obstetric cohort of more than 115,000 mother-neonate pairs from 25 hospitals (2008-2011). This analysis included women delivering singleton or twin births who experienced postpartum hemorrhage (estimated blood loss greater than 500 cc for vaginal delivery, estimated blood loss greater than 1,000 cc for cesarean delivery, or documented treatment for postpartum hemorrhage). Nighttime delivery was defined as that occurring between 8 PM and 6 AM. The primary outcome was a composite of maternal morbidity (death, hysterectomy, intensive care unit admission, transfusion, or unanticipated procedure for bleeding). Secondary outcomes included estimated blood loss, uterotonic use, and procedures to treat bleeding that occurred during the postpartum hospitalization. Multivariable logistic, linear, quantile, and multinomial regression models were used to assess associations between nighttime delivery and outcomes, adjusting for potential patient-level confounders and hospital as a fixed effect. RESULTS: In total, 2,709 (34.2%) of 7,917 women with postpartum hemorrhage delivered at night. Women who delivered at night were younger, had a lower body mass index, and were more likely to have government-sponsored insurance, be nulliparous, have hypertension, use neuraxial analgesia, and deliver vaginally. After adjusting for potential confounders, the primary composite outcome of maternal morbidity was similar regardless of night compared with day delivery (15.5% night vs 17.5% day; adjusted odds ratio 0.89, 95% CI 0.77-1.03). Some secondary outcomes, including mean EBL, frequency of uterotonic use, and time from delivery to first uterotonic dose, differed on unadjusted analyses, but these associations did not persist in multivariable analysis. The study had limited power to assess differences in uncommon outcomes. CONCLUSION: Nighttime delivery was not associated with significant differences in postpartum hemorrhage-related management or morbidity.

Incidence of early-onset sepsis in infants born to women with clinical chorioamnionitis.

Objective To determine the frequency of sepsis and other adverse neonatal outcomes in women with a clinical diagnosis of chorioamnionitis. Methods We performed a secondary analysis of a multi-center placebo-controlled trial of vitamins C/E to prevent preeclampsia in low risk nulliparous women. Clinical chorioamnionitis was defined as either the "clinical diagnosis" of chorioamnionitis or antibiotic administration during labor because of an elevated temperature or uterine tenderness in the absence of another cause. Early-onset neonatal sepsis was categorized as "suspected" or "confirmed" based on a clinical diagnosis with negative or positive blood, urine or cerebral spinal fluid cultures, respectively, within 72 h of birth. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Results Data from 9391 mother-infant pairs were analyzed. The frequency of chorioamnionitis was 10.3%. Overall, 6.6% of the neonates were diagnosed with confirmed (0.2%) or suspected (6.4%) early-onset sepsis. Only 0.7% of infants born in the setting of chorioamnionitis had culture-proven early-onset sepsis versus 0.1% if chorioamnionitis was not present. Clinical chorioamnionitis was associated with both suspected [OR 4.01 (3.16-5.08)] and confirmed [OR 4.93 (1.65-14.74)] early-onset neonatal sepsis, a need for resuscitation within the first 30 min after birth [OR 2.10 (1.70-2.61)], respiratory distress [OR 3.14 (2.16-4.56)], 1 min Apgar score of ≤3 [OR 2.69 (2.01-3.60)] and 4-7 [OR 1.71 (1.43-2.04)] and 5 min Apgar score of 4-7 [OR 1.67 (1.17-2.37)] (vs. 8-10). Conclusion Clinical chorioamnionitis is common and is associated with neonatal morbidities. However, the vast majority of exposed infants (99.3%) do not have confirmed early-onset sepsis.

Neonatal outcomes of elective early-term births after demonstrated fetal lung maturity.

BACKGROUND: Studies of early-term birth after demonstrated fetal lung maturity show that respiratory and other outcomes are worse with early-term birth (370-386 weeks) even after demonstrated fetal lung maturity when compared with full-term birth (390-406 weeks). However, these studies included medically indicated births and are therefore potentially limited by confounding by the indication for delivery. Thus, the increase in adverse outcomes might be due to the indication for early-term birth rather than the early-term birth itself. OBJECTIVE: We examined the prevalence and risks of adverse neonatal outcomes associated with early-term birth after confirmed fetal lung maturity as compared with full-term birth in the absence of indications for early delivery. STUDY DESIGN: This is a secondary analysis of an observational study of births to 115,502 women in 25 hospitals in the United States from 2008 through 2011. Singleton nonanomalous births at 37-40 weeks with no identifiable indication for delivery were included; early-term births after positive fetal lung maturity testing were compared with full-term births. The primary outcome was a composite of death, ventilator for ≥2 days, continuous positive airway pressure, proven sepsis, pneumonia or meningitis, treated hypoglycemia, hyperbilirubinemia (phototherapy), and 5-minute Apgar <7. Logistic regression and propensity score matching (both 1:1 and 1:2) were used. RESULTS: In all, 48,137 births met inclusion criteria; the prevalence of fetal lung maturity testing in the absence of medical or obstetric indications for early delivery was 0.52% (n = 249). There were 180 (0.37%) early-term births after confirmed pulmonary maturity and 47,957 full-term births. Women in the former group were more likely to be non-Hispanic white, smoke, have received antenatal steroids, have induction, and have a cesarean. Risks of the composite (16.1% vs 5.4%; adjusted odds ratio, 3.2; 95% confidence interval, 2.1-4.8 from logistic regression) were more frequent with elective early-term birth. Propensity scores matching confirmed the increased primary composite in elective early-term births: adjusted odds ratios, 4.3 (95% confidence interval, 1.8-10.5) for 1:1 and 3.5 (95% confidence interval, 1.8-6.5) for 1:2 matching. Among components of the primary outcome, CPAP use and hyperbilirubinemia requiring phototherapy were significantly increased. Transient tachypnea of the newborn, neonatal intensive care unit admission, and prolonged neonatal intensive care unit stay (>2 days) were also increased with early-term birth. CONCLUSION: Even with confirmed pulmonary maturity, early-term birth in the absence of medical or obstetric indications is associated with worse neonatal respiratory and hepatic outcomes compared with full-term birth, suggesting relative immaturity of these organ systems in early-term births.