Resistance to PRMT5-targeted therapy in mantle cell lymphoma.

ABSTRACT: Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma, and patients who relapse on targeted therapies have poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the antitumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient-derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor-resistant cells vs treatment-naive cells was observed (P = .005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n = 4; 50% inhibitory concentration [IC50], 20-140 nM) or primary resistant (n = 4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor-resistant cell lines (n = 4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50, suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term-treated cells, respectively, highlighted shared upregulation of multiple pathways including mechanistic target of rapamycin kinase [mTOR] signaling (P < 10-5 and z score > 0.3 or < 0.3). Single-cell RNA sequencing analysis demonstrated a strong shift in global gene expression, with upregulation of mTOR signaling in resistant PDX MCL samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor-resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.

Umbilical cord serum interleukin-6, C-reactive protein, and myeloperoxidase concentrations at birth and association with neonatal morbidities and long-term neurodevelopmental outcomes.

OBJECTIVE: The aim of the study is to determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children. STUDY DESIGN: Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP, and MPO levels, adverse newborn outcomes, and PTB < 32 weeks of gestational age (GA). RESULTS: Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for GA at delivery and treatment group. No significant associations between CRP or MPO and RDS, CLD, NEC, sepsis, or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (odds ratio, 0.10; 95% confidence interval, 0.02-0.41). No associations between umbilical cord IL-6, CRP, or MPO and MDI < 70 or PDI < 70 were evident. Umbilical cord serum concentrations of IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks of GA. CONCLUSION: Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for GA at delivery. Occurrence of levels > 75th percentile of IL-6, CRP, and MPO in umbilical cord serum was associated with PTB < 32 weeks of GA. Elevated umbilical cord serum concentrations of IL-6, CRP, and MPO at birth were not associated with poor neurodevelopmental outcomes.

Advanced lipoprotein measures and recurrent preterm birth.

OBJECTIVE: Lipoproteins are associated with atherogenic and inflammatory processes, and these processes may be related to adverse pregnancy outcomes. We therefore examined whether variations in lipoprotein particle size and concentration are associated with preterm birth (PTB) <35 weeks' gestation. STUDY DESIGN: This is a case-control ancillary study to a randomized trial of omega-3 fatty acid supplementation to prevent recurrent PTB. We measured standard lipids and used nuclear magnetic resonance (NMR) spectroscopy to characterize 17 lipoprotein particles from plasma collected at the baseline randomization visit (16-21 weeks' gestation) in 128 cases (PTB <35 weeks' gestation) and 132 term controls. Logistic regression models controlled for study center, race/ethnicity, number of prior PTB, smoking, and treatment group, as well as total low-density lipoprotein (LDL), high-density lipoprotein, and triglyceride concentrations when examining LDLNMR, high-density lipoproteinNMR, and very LDL (VLDL)NMR, respectively. RESULTS: Only 1 of the 17 NMR lipoproteins was associated with recurrent PTB. We observed an increased odds of recurrent PTB of 1.04 (95% confidence interval, 1.01-1.08; P = .02) per nanometer increase in VLDLNMR particle size and an odds ratio of 3.00 (confidence interval, 1.40-6.43; P = .005) for the third tertile of VLDLNMR particle size compared with the first tertile. CONCLUSION: In women with prior PTB, variations in midpregnancy lipoproteins were not associated with recurrent PTB overall, however the association observed with VLDLNMR particle size is suggestive that PTB may be amenable to lifestyle, nutritional, or pharmacologic interventions.

Gestational age-specific risks vs benefits of multicourse antenatal corticosteroids for preterm labor.

OBJECTIVE: The purpose of this study was to estimate a gestational age threshold at which the benefits of treatment with weekly courses of antenatal corticosteroids (ACS) during preterm labor outweigh the risks. STUDY DESIGN: Risk-benefit ratios by gestational age were determined with the use of a Markov microsimulation decision-analysis model with a 1-week cycle length. Single course and multiple (weekly to a maximum of 4) courses of ACS by gestational age of entry (23 weeks to 31 weeks 6 days' gestation) were compared. Benefits were composite events (respiratory distress syndrome, chronic lung disease, severe intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or stillbirth) averted. Risks were small head circumference and small for gestational age. RESULTS: More composite events are averted (benefits) than risks acquired (ratio, 6:1) when multiple courses of ACS are initiated at 26 weeks' gestation. When multiple courses of ACS are initiated at 29 weeks' gestation, the risk-benefit ratio is 1. Beyond 29 weeks, there is a suggestion of more risk than benefit. CONCLUSION: The model suggests that multiple courses of ACS that are initiated at <29 weeks' gestation may have increased benefit compared with risks. Further analyses are needed to determine the long-term clinical significance of these findings.

Maternal 25-hydroxyvitamin d and preterm birth in twin gestations.

OBJECTIVE: To assess whether there was an independent association between maternal 25-hydroxyvitamin D concentrations at 24-28 weeks of gestation and preterm birth in a multicenter U.S. cohort of twin pregnancies. METHODS: Serum samples from women who participated in a clinical trial of 17 α-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestations (2004-2006) were assayed for 25-hydroxyvitamin D concentrations using liquid chromatography tandem mass spectrometry (n=211). Gestational age was determined early in pregnancy using a rigorous algorithm. Preterm birth was defined as delivery of the first twin or death of either twin at less than 35 weeks of gestation. RESULTS: The mean serum 25-hydroxyvitamin D concentration was 82.7 nmol/L (standard deviation 31.5); 40.3% of women had concentrations less than 75 nmol/L. Preterm birth at less than 35 weeks of gestation occurred in 49.4% of women with 25-hydroxyvitamin D concentrations less than 75 nmol/L compared with 26.2% among those with concentrations of 75 nmol/L or more (P<.001). After adjustment for maternal race and ethnicity, study site, parity, prepregnancy body mass index, season, marital status, education, gestational age at blood sampling, smoking status, and 17 α-hydroxyprogesterone caproate treatment, maternal 25-hydroxyvitamin D concentration of 75 nmol/L or more was associated with a 60% reduction in the odds of preterm birth compared with concentrations less than 75 nmol/L (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.8). A similar protective association was observed when studying preterm birth at less than 32 weeks of gestation (OR 0.2, 95% CI 0.1-0.6) and after confounder adjustment. CONCLUSIONS: Late second-trimester maternal 25-hydroxyvitamin D concentrations less than 75 nmol/L are associated with an increase in the risk of preterm birth in this cohort of twin pregnancies. LEVEL OF EVIDENCE: II.

Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth.

OBJECTIVE: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-α, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS: Interleukin-10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-α Δ also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-α at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Δ and tumor necrosis factor-α Δ were unaffected by either omega-3 supplementation or fish diet. CONCLUSION: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: II.

Pregnancy outcomes with weight gain above or below the 2009 Institute of Medicine guidelines.

OBJECTIVE: To evaluate pregnancy outcomes according to 2009 Institute of Medicine (IOM) gestational weight gain guidelines. METHODS: This study is a secondary analysis of a preeclampsia prevention trial among nulliparas carrying singletons. Odds ratios and 95% confidence intervals (adjusted for maternal age, race, smoking, and treatment group) were calculated based on total weight gain below or above the IOM guidelines stratified by prepregnancy body mass index (BMI). The referent group was weight gain within the guidelines. RESULTS: Of 8,293 pregnancies, 9.5% had weight gain below, 17.5% within, and 73% above IOM guidelines. With excess weight gain, all BMI categories had an increased risk of hypertensive disorders; normal weight and overweight women also had increased risk of cesarean delivery and neonatal birth weight at or above the 90 centile but a decreased risk of weight below the 10 centile. There were no consistent associations with insufficient weight gain and adverse outcomes. CONCLUSION: Excess weight gain was prevalent and associated with an increased risk of hypertensive disorders, cesarean delivery, and large-for-gestational-age neonates.

Perinatal outcomes in Hispanic and non-Hispanic white women with mild gestational diabetes.

OBJECTIVE: To compare perinatal outcomes between self-identified Hispanic and non-Hispanic white women with mild gestational diabetes mellitus (GDM) or glucose intolerance. METHODS: In a secondary analysis of a mild GDM treatment trial, we compared perinatal outcomes by race and ethnicity for 767 women with glucose intolerance (abnormal 50-g 1-hour screen, normal 100-g 3-hour oral glucose tolerance test), 371 women with mild GDM assigned to usual prenatal care, and 397 women with mild GDM assigned to treatment. Outcomes included: composite adverse perinatal outcome (neonatal death, hypoglycemia, hyperbilirubinemia, hyperinsulinemia, stillbirth, birth trauma), gestational age at delivery, birth weight, and hypertensive disorders of pregnancy. Adjusted regression models included: 100-g 3-hour oral glucose tolerance test results, parity, gestational age, body mass index, maternal age at enrollment, and current tobacco use. RESULTS: The sample of 1,535 women was 68.3% Hispanic and 31.7% non-Hispanic white. Among women with glucose intolerance, Hispanic women had more frequent composite outcome (37% compared with 27%, adjusted odds ratio [OR] 1.62, 95% confidence interval [CI] 1.10-2.37) with more neonatal elevated C-cord peptide (19% compared with 13%, adjusted OR 1.79, 95% CI 1.04-3.08) and neonatal hypoglycemia (21% compared with 13%, adjusted OR 2.04, 95% CI 1.18-3.53). Among women with untreated mild GDM, outcomes were similar by race and ethnicity. Among Hispanic women with treated mild GDM, composite outcome was similar to non-Hispanic white women (35% compared with 25%, adjusted OR 1.62, 95% CI 0.92-2.86), but Hispanic neonates had more frequent hyperinsulinemia (21% compared with 10%, adjusted OR 2.96, 95% CI 1.33-6.60). CONCLUSION: Individual components of some neonatal outcomes were more frequent in Hispanic neonates, but most perinatal outcomes were similar between Hispanic and non-Hispanic ethnic groups. LEVEL OF EVIDENCE: II.

Relationship between 17-hydroxyprogesterone caproate concentrations and gestational age at delivery in twin gestation.

OBJECTIVE: We sought to evaluate in women with twin gestation the relationship between 17-hydroxyprogesterone caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action. STUDY DESIGN: Blood was obtained between 24-28 weeks (epoch 1) and 32-35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-hydroxyprogesterone, progesterone, C-reactive protein (CRP), and corticotrophin-releasing hormone were assessed. RESULTS: Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (P < .001). Women receiving 17-OHPC demonstrated significantly higher (P = .005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant (P < .0001) positive relationship was observed between 17-OHPC concentration and progesterone and 17-hydroxyprogesterone concentrations at both epochs. Corticotropin-releasing hormone concentrations did not differ by treatment group. CONCLUSION: 17-OHPC may adversely impact gestational age at delivery in women with twin gestation.

First-trimester prediction of preeclampsia in nulliparous women at low risk.

OBJECTIVE: To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia. METHODS: We conducted a multicenter observational study in 2,434 nulliparous women at low risk to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12, pregnancy-associated plasma protein-A, placental protein 13, placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 women in the control group. RESULTS: Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI, calculated as weight (kg)/[height (m)]), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later had development of preeclampsia (median 9.4 compared with 9.0 femtoliter (fl); P=.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 compared with 1.04; P=.003), pregnancy-associated plasma protein-A (0.94 compared with 0.98; P=.04), and placental growth factor (0.83 compared with 1.04; P<.001) were significantly different in women who had development of preeclampsia compared with women in the control group. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, pregnancy-associated plasma protein-A, and placental growth factor, and yielded an area under the curve of 0.73 (95% confidence interval 0.69-0.77) and a sensitivity of 46.1% (95% confidence interval 38.3-54.0) for 80% specificity. CONCLUSION: A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a nulliparous population at low risk. LEVEL OF EVIDENCE: II.

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.

Cytokine gene polymorphisms and length of gestation.

OBJECTIVE: To estimate whether there is an association between length of gestation and gene polymorphisms that effect transcription of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), or interleukin-1ß (IL-1ß). METHODS: Blood for DNA analysis was collected from 834 women at high risk enrolled in a randomized, clinical trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. Genotyping was performed for three single nucleotide polymorphisms (SNPs), TNF-α -308, IL-6 -174, and IL-1ß +3954. Women with the homozygous minor genotype were compared with women with either the heterozygous or the homozygous major genotype. Kaplan-Meier curves of gestational age at delivery and odds ratios for extreme preterm delivery were adjusted for African-American race and treatment group. RESULTS: Women who were homozygous for the minor allele at the -308 position in the promoter region of the TNF-α gene had significantly shorter length of gestation than women who were either heterozygous or homozygous for the major allele (adjusted hazard ratio 1.74, 95% confidence interval [CI] 1.04-2.90, P=.03). Among women with this genotype, 20% (3/15) experienced extreme spontaneous preterm delivery (less than 28 weeks of gestation; adjusted odds ratio 7.51, 95% CI 1.84-30.72, P=.005). There was no difference in length of gestation or risk of extreme spontaneous preterm delivery by genotype for the IL-6 -174 or the IL-1ß +3954 SNP. CONCLUSION: Polymorphism at the -308 position in the TNF-α promoter region is associated with shorter gestation and an increased risk of spontaneous extreme preterm delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: II.

Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes.

Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery.

Neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm, and term.

We compared neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth. A secondary analysis of a multicenter, randomized controlled trial of multiple gestations was conducted. MPTB was defined as delivery between 32 (0)/(7) and 33 (6)/(7) weeks and LPTB between 34 (0)/(7) and 36 (6)/(7) weeks. Primary outcome was a neonatal outcome composite consisting of one or more of the following: neonatal death, respiratory distress syndrome, early onset culture-proven sepsis, stage 2 or 3 necrotizing enterocolitis, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, pneumonia, or severe retinopathy of prematurity. Among 552 twin pregnancies, the MPTB rate was 14.5%, LPTB 49.8%, and term birth rate 35.7%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term birth ( P < 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following MPTB (relative risk [RR] 58.5; 95% confidence interval [CI] 11.3 to 1693.0) and LPTB (RR 24.9; 95% CI 4.8 to 732.2). Twin pregnancies born moderately and late preterm encounter higher rates of neonatal morbidities compared with twins born at term.

The effect of maternal body mass index on neonatal outcome in women receiving a single course of antenatal corticosteroids.

OBJECTIVE: The aim of this study was to determine the effect of maternal body mass index on the incidence of neonatal prematurity morbidities in those who receive corticosteroids. STUDY DESIGN: This was a secondary analysis of a trial of corticosteroids in women at risk for preterm birth. Women receiving a single course of corticosteroids were classified by their prepregnancy body mass index (<25 and > or = 25) and compared on a composite outcome comprised of several neonatal morbidities and on each individual outcome. RESULTS: Of 183 eligible women, 96 (52.5%) had a body mass index of <25 and 87 (47.5%) had a body mass index of > or = 25. The composite outcome occurred more frequently in the body mass index of > or = 2 5 group (28.7%), compared with those with a body mass index of <25 (18.8%), although this was not statistically significant (odds ratio, 1.75; 95% confidence interval, 0.83-3.72). Body mass index was not associated with outcomes after adjusting for confounding. CONCLUSION: Maternal body mass index did not affect neonatal prematurity morbidities in those receiving corticosteroids.

Bone metabolism in pregnant women exposed to single compared with multiple courses of corticosteroids.

OBJECTIVE: To compare markers of maternal bone metabolism between women who received a single compared with multiple courses of antenatal corticosteroids. METHODS: This is an analysis of serum samples from a previously reported randomized, placebo-controlled, multicenter trial. Women at risk for preterm delivery after an initial course of corticosteroids were randomly assigned to weekly courses of betamethasone (active) or placebo. Serum levels of carboxy terminal propeptide of type I procollagen (PICP) and cross-linked carboxy terminal telopeptide of type I collagen (ICTP) were measured to assess the rate of bone formation and resorption, respectively, at three time points. The placebo group (n=93) was compared with the active group, receiving four or more courses of betamethasone (n=112). RESULTS: There were significant (P<.001) increases in PICP and ICTP between baseline and delivery in both groups. Cross-linked carboxy terminal telopeptide of type I collagen, but not PICP, was lower with corticosteroid exposure immediately before administration of the fourth study course (P<.001). No significant differences in PICP and ICTP were seen between groups at delivery. CONCLUSION: Increasing levels of PICP and ICTP with advancing gestation are consistent with physiologic changes in maternal bone metabolism. Multiple courses of corticosteroids for fetal maturation are not associated with persistent or cumulative effects on maternal bone metabolism as measured by PICP and ICTP. LEVEL OF EVIDENCE: II.

Comparison of maternal and infant outcomes from primary cesarean delivery during the second compared with first stage of labor.

OBJECTIVE: To compare maternal and neonatal outcomes when primary cesarean delivery is performed in the second stage of labor compared with the first stage. METHODS: Between January 1, 1999, and December 31, 2000, a prospective observational study of primary cesarean deliveries was conducted at 13 university centers comprising the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The primary outcomes of interest included a maternal composite (composed of at least one of the following: endometritis, intraoperative surgical complication, blood transfusion, or wound complication) and neonatal composite (which included at least one of the following: Apgar score of 3 or less at 5 minutes, neonatal death, neonatal intensive care unit admission, seizure, delivery room intubation in the absence of meconium, or fetal injury). RESULTS: A total of 11,981 cesarean deliveries were available for analysis: 9,265 were performed in the first stage and 2,716 in the second stage. Cesarean deliveries performed in the second stage were associated with longer operative times, epidural analgesia, chorioamnionitis, and higher birth weight (all P<.001). The maternal composite index was slightly increased in women undergoing cesarean delivery in the second stage of labor, primarily due to uterine atony, uterine incision extension, and incidental cystotomy. This difference was significant after multivariable analysis (odds ratio 1.21, 95% confidence interval 1.07-1.37). After multivariable analysis, the neonatal composite did not differ significantly between groups (odds ratio 0.96, 95% confidence interval 0.84-1.08). CONCLUSION: Cesarean delivery in the second stage of labor is associated with slightly increased maternal but not neonatal composite morbidity. LEVEL OF EVIDENCE: II.

Fetal injury associated with cesarean delivery.

OBJECTIVE: To describe the incidence and type of fetal injury identified in women undergoing cesarean delivery. METHODS: Between January 1, 1999, and December 31, 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 university centers. Information regarding maternal and infant outcomes was abstracted directly from hospital charts. RESULTS: A total of 37,110 cesarean deliveries were included in the registry, and 418 (1.1%) had an identified fetal injury. The most common injury was skin laceration (n = 272, 0.7%). Other injuries included cephalohematoma (n = 88), clavicular fracture (n = 11), brachial plexus (n = 9), skull fracture (n = 6), and facial nerve palsy (n = 11). Among primary cesarean deliveries, deliveries with a failed forceps or vacuum attempt had the highest rate of injuries (6.9%). In women with a prior cesarean delivery, the highest rate of injury also occurred in the unsuccessful trial of forceps or vacuum (1.7%), and the lowest rate occurred in the elective repeat cesarean group (0.5%). The type of uterine incision was associated with fetal injury, 3.4% "T" or "J" incision, 1.4% for vertical incision, and 1.1% for a low transverse (P = .003), as was a skin incision-to-delivery time of 3 minutes or less. Fetal injury did not vary in frequency with the type of skin incision, preterm delivery, maternal body mass index, or infant birth weight greater than 4,000 g. CONCLUSION: Fetal injuries complicate 1.1% of cesarean deliveries. The frequency of fetal injury at cesarean delivery varies with the indication for surgery as well as with the duration of the skin incision-to-delivery interval and the type of uterine incision. LEVEL OF EVIDENCE: II-3.

Maternal morbidity associated with multiple repeat cesarean deliveries.

OBJECTIVE: Although repeat cesarean deliveries often are associated with serious morbidity, they account for only a portion of abdominal deliveries and are overlooked when evaluating morbidity. Our objective was to estimate the magnitude of increased maternal morbidity associated with increasing number of cesarean deliveries. METHODS: Prospective observational cohort of 30,132 women who had cesarean delivery without labor in 19 academic centers over 4 years (1999-2002). RESULTS: There were 6,201 first (primary), 15,808 second, 6,324 third, 1,452 fourth, 258 fifth, and 89 sixth or more cesarean deliveries. The risks of placenta accreta, cystotomy, bowel injury, ureteral injury, and ileus, the need for postoperative ventilation, intensive care unit admission, hysterectomy, and blood transfusion requiring 4 or more units, and the duration of operative time and hospital stay significantly increased with increasing number of cesarean deliveries. Placenta accreta was present in 15 (0.24%), 49 (0.31%), 36 (0.57%), 31 (2.13%), 6 (2.33%), and 6 (6.74%) women undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries, respectively. Hysterectomy was required in 40 (0.65%) first, 67 (0.42%) second, 57 (0.90%) third, 35 (2.41%) fourth, 9 (3.49%) fifth, and 8 (8.99%) sixth or more cesarean deliveries. In the 723 women with previa, the risk for placenta accreta was 3%, 11%, 40%, 61%, and 67% for first, second, third, fourth, and fifth or more repeat cesarean deliveries, respectively. CONCLUSION: Because serious maternal morbidity increases progressively with increasing number of cesarean deliveries, the number of intended pregnancies should be considered during counseling regarding elective repeat cesarean operation versus a trial of labor and when debating the merits of elective primary cesarean delivery. LEVEL OF EVIDENCE: II-2.