Evaluation of Hypoglycemia in Neonates of Women at Risk for Late Preterm Delivery: An Antenatal Late Preterm Steroids Trial Cohort Study.

OBJECTIVE: In the antenatal late preterm steroids (ALPS) trial betamethasone significantly decreased short-term neonatal respiratory morbidity but increased the risk of neonatal hypoglycemia, diagnosed only categorically (<40 mg/dL). We sought to better characterize the nature, duration, and treatment for hypoglycemia. STUDY DESIGN: Secondary analysis of infants from ALPS, a multicenter trial randomizing women at risk for late preterm delivery to betamethasone or placebo. This study was a reabstraction of all available charts from the parent trial, all of which were requested. Unreviewed charts included those lost to follow-up or from sites not participating in the reabstraction. Duration of hypoglycemia (<40 mg/dL), lowest value and treatment, if any, were assessed by group. Measures of association and regression models were used where appropriate. RESULTS: Of 2,831 randomized, 2,609 (92.2%) were included. There were 387 (29.3%) and 223 (17.3%) with hypoglycemia in the betamethasone and placebo groups, respectively (relative risk [RR]: 1.69, 95% confidence interval [CI]: 1.46-1.96). Hypoglycemia generally occurred in the first 24 hours in both groups: 374/385 (97.1%) in the betamethasone group and 214/222 (96.4%) in the placebo group (p = 0.63). Of 387 neonates with hypoglycemia in the betamethasone group, 132 (34.1%) received treatment, while 73/223 (32.7%) received treatment in placebo group (p = 0.73). The lowest recorded blood sugar was similar between groups. Most hypoglycemia resolved by 24 hours in both (93.0 vs. 89.3% in the betamethasone and placebo groups, respectively, p = 0.18). Among infants with hypoglycemia in the first 24 hours, the time to resolution was shorter in the betamethasone group (2.80 [interquartile range: 2.03-7.03) vs. 3.74 (interquartile range: 2.15-15.08) hours; p = 0.002]. Persistence for >72 hours was rare and similar in both groups, nine (2.4%, betamethasone) and four (1.9%, placebo, p = 0.18). CONCLUSION: In this cohort, hypoglycemia was transient and most received no treatment, with a quicker resolution in the betamethasone group. Prolonged hypoglycemia was uncommon irrespective of steroid exposure. KEY POINTS: · Hypoglycemia was transient and approximately two-thirds received no treatment.. · Neonates in the ALPS trial who received betamethasone had a shorter time to resolution than those with hypoglycemia in the placebo group.. · Prolonged hypoglycemia occurred in approximately 2 out of 100 late preterm newborns, irrespective of antenatal steroid exposure..

The Association of Cesarean Skin Incision Length and Postoperative Wound Complications.

OBJECTIVE: This study was aimed to evaluate the relationship between cesarean skin incision length and wound complications. STUDY DESIGN: Planned secondary analysis of a multicenter double-blind randomized trial of adjunctive azithromycin versus placebo (in addition to standard cefazolin) in women ≥24 weeks undergoing cesarean delivery during labor or ≥4 hours after membrane rupture. Skin incision length (cm) was measured just prior to skin closure. The primary outcome was a composite of wound complications (wound infection, separation, seroma, hematoma, or dehiscence) up to 6 weeks of postpartum. Individual components of the composite were examined as secondary outcomes. Outcomes were compared between groups defined by the lowest (≤25th), middle (25-75th) and highest (>75th) incision length quartiles. Logistic regression was used to adjust for potential confounding variables. RESULTS: Of the 2,013 women enrolled in the primary trial, 1,916 had recorded incision lengths and were included in this secondary analysis. The overall rate of composite wound complications was 7.8%. Median incision length was 15.0 cm (interquartile range: 14.0-16.5) with the lowest quartile defined as ≤14, middle as >14 to ≤16.5, and highest as >16.5 cm. Mean BMI, parity, use of staples, and duration of surgery differed significantly between the three incision length groups. In unadjusted analysis, the longest incision lengths were associated with an increased risk of the wound composite and wound infections (odds ratio [OR] = 2.27, 95% confidence interval [CI]: 1.43-3.60 and OR = 2.30, 95% CI: 1.27-4.15, respectively) compared with the shortest incision lengths. However, after multivariable adjustments, these associations were nullified. Additional analyses considering incision length as a continuous variable and using 10th/90th percentile cut-offs still did not suggest any associations with outcomes. CONCLUSION: Increasing skin incision length is not independently associated with an increased risk of postoperative wound complications. KEY POINTS: · After multivariable adjustments, skin incision length was not independently associated with an increased risk of postoperative wound complications.. · A reasonable incision length needed to safely perform the procedure should be used..

Outpatient Cervical Ripening: A Cost-Minimization and Threshold Analysis.

OBJECTIVE: To evaluate cost of outpatient (OP) versus inpatient (IP) ripening with transcervical balloons, and determine circumstances in which each strategy would be cost saving. STUDY DESIGN: We created a decision model comparing OP and IP balloon ripening in term (≥37 weeks) singleton pregnancies with unfavorable cervix. We performed a cost-minimization analysis and threshold analyses comparing two OP ripening strategies (broad and limited use) to IP ripening from a health system perspective. Base case estimates of probability, utilization, and cost were derived from the literature. The primary outcome was incremental cost of OP versus IP ripening from a hospital perspective. One- and two-way sensitivity analyses explored uncertainty in the model. RESULTS: Both OP ripening strategies were cost saving compared with IP ripening: incremental cost -$228.40/patient with broad use and -$73.48/patient with limited use. OP ripening was no longer cost saving if hours saved on labor and delivery (L&D) were <3.5, insertion visit cost >$714, or facility cost/hour on L&D <$61. Two-way sensitivity analyses showed that OP ripening was cost saving under the most plausible clinical circumstances. CONCLUSION: In patients with unfavorable cervix, OP transcervical balloon ripening was cost saving under a wide range of circumstances, particularly if OP ripening can shorten time spent on L&D by 3.5 hours.

Association Between Features of Spontaneous Late Preterm Labor and Late Preterm Birth.

OBJECTIVE: This study aimed to evaluate the association between clinical and examination features at admission and late preterm birth. STUDY DESIGN: The present study is a secondary analysis of a randomized trial of singleton pregnancies at 340/7 to 365/7 weeks' gestation. We included women in spontaneous preterm labor with intact membranes and compared them by gestational age at delivery (preterm vs. term). We calculated a statistical cut-point optimizing the sensitivity and specificity of initial cervical dilation and effacement at predicting preterm birth and used multivariable regression to identify factors associated with late preterm delivery. RESULTS: A total of 431 out of 732 (59%) women delivered preterm. Cervical dilation ≥ 4 cm was 60% sensitive and 68% specific for late preterm birth. Cervical effacement ≥ 75% was 59% sensitive and 65% specific for late preterm birth. Earlier gestational age at randomization, nulliparity, and fetal malpresentation were associated with late preterm birth. The final regression model including clinical and examination features significantly improved late preterm birth prediction (81% sensitivity, 48% specificity, area under the curve = 0.72, 95% confidence interval [CI]: 0.68-0.75, and p-value < 0.01). CONCLUSION: Four in 10 women in late-preterm labor subsequently delivered at term. Combination of examination and clinical features (including parity and gestational age) improved late-preterm birth prediction.

Antenatal Betamethasone for Women at Risk for Late Preterm Delivery.

BACKGROUND: Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. METHODS: We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. RESULTS: The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). CONCLUSIONS: Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.).

Risk Factors, Etiologies, and Screening Tools for Sepsis in Pregnant Women: A Multicenter Case-Control Study.

BACKGROUND: Given the significant morbidity and mortality of maternal sepsis, early identification is key to improve outcomes. This study aims to evaluate the performance characteristics of the systemic inflammatory response syndrome (SIRS), quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA), and maternal early warning (MEW) criteria for identifying cases of impending sepsis in parturients. The secondary objective of this study is to identify etiologies and risk factors for maternal sepsis and to assess timing of antibiotics in patients diagnosed with sepsis. METHODS: Validated maternal sepsis cases during the delivery hospitalization from 1995 to 2012 were retrospectively identified at 7 academic medical centers in the United States and Israel. Control patients were matched by date of delivery in a 1:4 ratio. The sensitivity and specificity of SIRS, qSOFA, and MEW criteria for identifying sepsis were calculated. Data including potential risk factors, vital signs, laboratory values, and clinical management were collected for cases and controls. RESULTS: Eighty-two sepsis cases during the delivery hospitalization were identified and matched to 328 controls. The most common causes of sepsis were the following: chorioamnionitis 20 (24.4%), endometritis 19 (23.2%), and pneumonia 9 (11.0%). Escherichia coli 12 (14.6%), other Gram-negative rods 8 (9.8%), and group A Streptococcus 6 (7.3%) were the most commonly found pathogens. The sensitivities and specificities for meeting criteria for screening tools were as follows: (1) SIRS (0.93, 0.63); (2) qSOFA (0.50, 0.95); and (3) MEW criteria for identifying sepsis (0.82, 0.87). Of 82 women with sepsis, 10 (12.2%) died. The mortality rate for those who received antibiotics within 1 hour of diagnosis was 8.3%. The mortality rate was 20% for the patients who received antibiotics after >1 hour. CONCLUSIONS: Chorioamnionitis and endometritis were the most common causes of sepsis, together accounting for about half of cases. Notable differences were observed in the sensitivity and specificity of sepsis screening tools with the highest to lowest sensitivity being SIRS, MEW, and qSOFA criteria, and the highest to lowest specificity being qSOFA, MEW, and SIRS. Mortality was doubled in the cohort of patients who received antibiotics after >1 hour. Clinicians need to be vigilant to identify cases of peripartum sepsis early in its course and prioritize timely antibiotic therapy.

Neonatal Outcomes Associated with Umbilical Cord Milking in Preterm Multiple Gestations.

OBJECTIVE: Our aim was to evaluate the effect of umbilical cord milking on outcomes for preterm multiples. STUDY DESIGN: We implemented a policy of cord milking in neonates born at less than 30 weeks' gestation in September 2011. We compared cord milking in multiples with a historical cohort. Multivariable logistic regression models estimated the effect of cord milking on a composite neonatal adverse outcome. Secondary outcomes were hematocrit at birth, need for blood transfusion, and inotrope use. RESULTS: We identified 149 neonates (120 twins, 29 triplets), 51 historical controls, and 98 neonates with cord milking. Cord milking was associated with a lower rate of adverse composite neonatal outcome in univariable analysis (odds ratio [OR]: 0.36; 95% confidence interval [CI]: 0.15-0.84). However, in multivariable modeling, the effect was not significant (adjusted OR [aOR]: 0.54, 95% CI: 0.23-1.28). Hematocrit was 4.6 unit % (95% CI: 2-7.3) higher in the cord milking group, and cord milking was associated with a lower rate of blood transfusion (aOR: 0.28; 95% CI: 0.1-0.74; p = 0.01). There was no difference in inotrope administration. CONCLUSION: Umbilical cord milking was not associated with a decrease in composite neonatal adverse outcome. However, we observed an increase in hematocrit and decreased need for blood transfusion in neonates with cord milking.

Incidence and Risk Factors for Hospital Readmission or Unexpected Visits in Women Undergoing Unscheduled Cesarean Delivery.

OBJECTIVE: Hospital readmissions are increasingly tracked and assessed for value-based compensation. Our objective was to determine the incidence and risk factors associated with post-cesarean delivery (CD) readmissions or unexpected visits, defined as unexpected office or emergency room visits. STUDY DESIGN: This is a secondary analysis of a multicenter randomized controlled trial of adjunctive azithromycin prophylaxis for CD performed in laboring patients with viable pregnancies. Patients were followed up to 6 weeks postpartum. Our primary outcome was a composite of hospital readmission or unexpected visit, defined as unscheduled clinic or emergency department visits. Data of hospital readmissions, unexpected visits, and their reasons were collected. Demographics, antepartum, intrapartum, and postpartum risk factors were evaluated in bivariate analyses and multivariable logistic regression modeling. RESULTS: A total of 1,019 women were randomized to azithromycin and 994 to placebo. The prevalence of readmission or unexpected visit was 10.2% (95% confidence interval [CI]: 8.9-11.6), with rates of 3.8% (95% CI: 3.0-4.7%) hospital readmissions, 6.9% (95% CI: 5.8-8.0%) emergency room visits, and 4.2% (95% CI: 3.4-5.2%) unexpected clinic visits. The most common causes were infectious disease and hypertensive disorder. Women with readmissions or unexpected visits were more likely to be obese and diabetic, as well as experience longer length of ruptured membranes, intrauterine pressure catheter placement, and postpartum fevers. On multivariable analysis, diabetes (adjusted odds ratio [aOR]: 1.6, 95% CI: 1.1-2.4), prolonged ruptured membranes (aOR: 1.9, 95% CI: 1.3-2.8), and postpartum fevers (aOR: 4.6, 95% CI: 3.0-7.0) were significantly positively associated with readmission or unscheduled visit, while azithromycin was a protective (aOR: 0.6, 95% CI: 0.5-0.9). CONCLUSION: Women who had postpartum fever were at especially high risk for readmission or unexpected visits. Diabetes, prolonged ruptured membranes, and postpartum fevers were significantly associated with the adverse outcome, and azithromycin was associated with lower rates of readmission and unexpected visits.

Impact of Azithromycin-Based Extended-Spectrum Antibiotic Prophylaxis on Noninfectious Cesarean Wound Complications.

OBJECTIVE: Adding azithromycin to standard antibiotic prophylaxis for unscheduled cesarean delivery has been shown to reduce postcesarean infections. Because wound infection with ureaplasmas may not be overtly purulent, we assessed the hypothesis that azithromycin-based extended-spectrum antibiotic prophylaxis also reduces wound complications that are identified as noninfectious. STUDY DESIGN: This is a secondary analysis of the C/SOAP (Cesarean Section Optimal Antibiotic Prophylaxis) randomized controlled trial, which enrolled women with singleton pregnancies ≥24 weeks who were undergoing nonelective cesarean. Women were randomized to adjunctive azithromycin or identical placebo up to 1 hour preincision. All wound complications occurring within 6 weeks were adjudicated into infection and noninfectious wound complications (seroma, hematoma, local cellulitis, and other noninfectious wound breakdown). The primary outcome for this analysis is the composite of noninfectious wound complications. RESULTS: At a total of 14 sites, 2,013 women were randomized to adjunctive azithromycin (n = 1,019) or placebo (n = 994). Groups were similar at baseline. Although there was a lower rate of noninfectious wound complications in the azithromycin group compared with placebo (2.9 vs. 3.8%), this was not statistically significant (p = 0.22). CONCLUSION: While adding azithromycin to usual antibiotic prophylaxis for nonelective cesarean delivery does reduce the risk of postcesarean infections, it did not significantly reduce the risk of postcesarean noninfectious wound complications.

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.

The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth.

Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10% of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3% for GA and a broad-sense heritability of 24.5%. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2% of the variance of GA, and the remaining 60.3% is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention.

Effect of umbilical cord milking on morbidity and survival in extremely low gestational age neonates.

OBJECTIVE: Delayed umbilical cord clamping benefits extremely low gestational age neonates (ELGANs) but has not gained wide acceptance. We hypothesized that milking the umbilical cord (MUC) would avoid resuscitation delay but improve hemodynamic stability and reduce rates for composite outcome of severe intraventricular hemorrhage, necrotizing enterocolitis, and/or death before discharge. STUDY DESIGN: We implemented a joint neonatal/maternal-fetal quality improvement process for MUC starting September 2011. The MUC protocol specified that infants who were born at <30 weeks of gestation undergo MUC 3 times over a duration of <30 seconds at delivery. Obstetric and neonatal data were collected until discharge. We compared the MUC group to retrospective ELGAN cohort delivered at our center between January 2010 and August 2011. Analysis was intention-to-treat. RESULTS: We identified 318 ELGANs: 158 eligible for MUC and 160 retrospective control neonates. No adverse events were reported with cord milking. There was no difference in neonatal resuscitation, Apgar scores, or admission temperature. Hemodynamic stability was improved in the MUC group with higher mean blood pressures through 24 hours of age, despite less vasopressor use (18% vs 32%; P < .01). The initial hematocrit value was higher (50% vs 45%; P < .01), and red cell transfusions were fewer (57% vs 79%; P < .01) in MUC vs control infants. Presence of the composite outcome was significantly less in MUC vs the historic control infants (22% v 39%; odds ratio, 1.81; 95% confidence interval, 1.06-3.10). There were also reductions in intraventricular hemorrhage, necrotizing enterocolitis, and death before hospital discharge. CONCLUSION: MUC improves early hemodynamic stability and is associated with lower rates of serious morbidity and death among ELGANs.

Intrapartum magnesium sulfate and the potential for cardiopulmonary drug-drug interactions.

BACKGROUND: This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). METHODS: Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied, if they received 1 or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids/laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which were contraindicated for patients receiving MgSO4. RESULTS: Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids/laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P < 0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared with 0 of 618 (0%) women who did not receive furosemide (Fisher exact test, P < 0.001). CONCLUSIONS: Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications.

Prevention of recurrent preterm birth: role of the neonatal follow-up program.

Preterm birth (PTB) is a public health crisis in need of effective preventative strategies. Multi-disciplinary Neonatal Follow-up Programs (NFPs) provide health services to preterm infants at high risk for developmental problems after discharge from US newborn intensive care units. We aimed to determine whether NFPs are a potentially effective venue for specialized maternal counseling and intervention aimed at reducing the high rate of recurrent PTB in this population. This prospective case series enrolled women with preterm children evaluated in the Utah Department of Health NFP, 2010-2012. Women were interviewed, received Maternal Fetal Medicine (MFM) counseling services, and maternal and neonatal records were abstracted. We assessed maternal demographics, medical history, and characteristics of the index pregnancy. We calculated the proportion of women with knowledge of PTB recurrence risk and available prevention strategies, and assessed current contraceptive use and reproductive plans. Ninety-six women with a history of early PTB (≤26 weeks and/or birth weight < 1,250 g) were evaluated. Nearly 1 in 5 women (19.8 %) evaluated reported sexual activity, desire to avoid pregnancy, and no current contraceptive use, and were therefore at imminent risk of unintended pregnancy. Of women without permanent contraception, only 24.3 % were aware of their individual PTB recurrence risk. Of women with a history of spontaneous PTB, only 4 % were aware of effective pharmacologic preventative strategies. Introduction of MFM consultation as part NFP multi-disciplinary services is a novel approach with the potential to reduce recurrent PTB in an exceptionally high-risk population.

Neonatal outcomes in term and preterm infants following adjunctive azithromycin antibiotic prophylaxis for non-elective cesarean delivery.

OBJECTIVE: It is currently unknown whether adjunctive azithromycin prophylaxis at the time of non-elective cesarean has differential effects on neonatal outcomes in the context of prematurity. The objective of this study was to compare whether neonatal outcomes differ in term and preterm infants exposed to adjunctive azithromycin prophylaxis before non-elective cesarean delivery. STUDY DESIGN: A planned secondary analysis of a multi-center randomized controlled trial that enrolled women with singleton pregnancies ≥24 weeks gestation undergoing non-elective cesarean delivery (during labor or ≥4 h after membrane rupture). Women received standard antibiotic prophylaxis and were randomized to either adjunctive azithromycin (500 mg) or placebo. The primary composite outcome was neonatal death, suspected or confirmed neonatal sepsis, and serious neonatal morbidities (NEC, PVL, IVH, BPD). Secondary outcomes included NICU admission, neonatal readmission, culture positive infections and prevalence of resistant organisms. Odds ratios (OR) for the effect of azithromycin versus placebo were compared between gestational age strata (preterm [less than 37 weeks] versus term [37 weeks or greater]). Tests of interaction examined homogeneity of treatment effect with gestational age. RESULTS: The analysis includes 2,013 infants, 226 preterm (11.2%) and 1,787 term. Mean gestational ages were 34 and 39.5 weeks, respectively. Within term and preterm strata, maternal and delivery characteristics were similar between the azithromycin and placebo groups. There was no difference in the odds of composite neonatal outcome between those exposed to azithromycin versus placebo in preterm neonates (OR 0.82, 95% CI 0.48-1.41) and in term neonates (OR 1.06, 95% CI 0.77-1.46), with no difference between gestational age strata (p = 0.42). Analysis of secondary outcomes also revealed no differences in treatment effects within or between gestational age strata. CONCLUSION: Exposure to adjunctive azithromycin antibiotic prophylaxis for non-elective cesarean delivery does not increase neonatal morbidity or mortality in term or preterm infants. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01235546.

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis.

BACKGROUND: Because of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB. RESULTS: We reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 - 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity. CONCLUSIONS: IL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.Population structure is an important confounding factor that should be controlled for in studies of PTB.

Performance of a Multianalyte 'Rule-Out' Assay in Pregnant Individuals With Suspected Preeclampsia.

BACKGROUND: The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia. METHODS: Prospective, multicenter cohort study of pregnant individuals presenting between 280/7 and 366/7 weeks' with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model. RESULTS: One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%-33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank P<0.0001; adjusted hazard ratio of 4.81 [3.69-6.27, P<0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%-83.5%), negative predictive value 95.0% (92.8%-96.6%), and negative likelihood ratio 0.46 (0.32-0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks. CONCLUSIONS: We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment. REGISTRATION: The study was registered on Clinicaltrials.gov (Identifier NCT02780414).

Long-term maternal morbidity associated with repeat cesarean delivery.

Concern regarding the association between cesarean delivery and long-term maternal morbidity is growing as the rate of cesarean delivery continues to increase. Observational evidence suggests that the risk of morbidity increases with increasing number of cesarean deliveries. The dominant maternal risk in subsequent pregnancies is placenta accreta spectrum disorder and its associated complications. A history of multiple cesarean deliveries is the major risk factor for this condition. Pregnancies following cesarean delivery also have increased risk for other types of abnormal placentation, reduced fetal growth, preterm birth, and possibly stillbirth. Chronic maternal morbidities associated with cesarean delivery include pelvic pain and adhesions. Adverse reproductive effects may include decreased fertility and increased risk of spontaneous abortion and ectopic pregnancy. Clinicians and patients need to be aware of the long-term risks associated with cesarean delivery so that they can be considered when determining the method of delivery for first and subsequent births.

Repeated course antenatal steroids, inflammation gene polymorphisms, and neurodevelopmental outcomes at age 2.

OBJECTIVE: We sought to evaluate the interaction between repeated-course antenatal corticosteroids and inflammation gene polymorphisms with neurodevelopmental outcomes at age 2 years. STUDY DESIGN: We conducted nested case-control analysis of a randomized controlled trial of single- vs repeated-course antenatal corticosteroids. Cases had mental and/or psychomotor delay at age 2 years. Controls had normal neurodevelopment. Previous analyses of 125 cases and 147 controls identified 4 inflammation gene polymorphisms associated with neurodevelopmental delay at age 2 years. RESULTS: The interaction between repeated-course corticosteroids and the interleukin (IL)-6 -174 genotype with neurodevelopmental delay was significant (P = .046). The IL-6 -174 GG genotype was associated with neurodevelopmental delay at age 2 years in the single-course corticosteroid group (odds ratio, 6.47; 95% confidence interval, 1.86-22.50). Exposure to repeated-course antenatal corticosteroids abrogated this genotype effect (odds ratio, 1.30; 95% confidence interval, 0.48-3.54). Results were unchanged after controlling for potential confounders. CONCLUSION: Repeated-course antenatal steroids may reduce the increased risk of neurodevelopmental delay at age 2 years associated with IL-6 -174 GG genotype.

Impact of preterm PROM and its complications on long-term infant outcomes.

There is increasing evidence that preterm premature rupture of membranes (PPROM) is associated with increased risk for adverse neurodevelopmental outcomes through multiple mechanisms, including preterm birth and its antecedent etiologies. Intrauterine infection is a particularly important risk factor for adverse neurodevelopmental outcomes after PPROM. This review focuses on the long-term neurodevelopmental outcomes after PPROM, the possible etiologic mechanisms of neurological injury, and the effect of antenatal and perinatal interventions using available evidence.