Antenatal Magnesium and Cerebral Palsy in Preterm Infants.

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

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.

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.

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.

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.

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.

Screening and diagnosis of gestational diabetes mellitus.

Screening, diagnosis, and treatment of gestational diabetes mellitus (GDM) are common practice, despite controversy regarding benefits. A review of the literature from 1950 to 2006 revealed 3 randomized controlled trials evaluated the treatment of GDM but 2 of these studies lacked power to detect a difference in outcomes. The single trial with sufficient power showed a 67% lower rate of serious perinatal complication (a composite of shoulder dystocia, nerve injury, fracture, and death) and a 53% lower rate of macrosomia with treatment of GDM. There are no well-designed studies evaluating screening or diagnostic strategies. Treatment of GDM may improve some neonatal and obstetric outcomes, but there is limited evidence useful for determining the best screening method or diagnostic test, strategy, and criteria. Ongoing studies may provide some evidence to guide future research and clinical practice.

Acquired von Willebrand disease: management of labor and delivery with intravenous dexamethasone, continuous factor concentrate, and immunoglobulin infusion.

Acquired von Willebrand disease is a rare bleeding disorder that can lead to complete absence of clotting factor 8 and von Willebrand factor. Recently, the hematologic literature has reported continuous infusion of factor concentrates and intravenous immunoglobulin as an improved therapy for active bleeding and prophylaxis in patients who are anticipating surgery with congenital von Willebrand disease. We describe the first case of a pregnant woman with acquired von Willebrand disease who underwent the described therapy during delivery.