Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids.

OBJECTIVE: The aim of the study is to evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA), and response to repeat ACS. STUDY DESIGN: This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), continuous positive airway pressure (CPAP)/ventilator use (CPV), and SGA. RESULTS: CRHBP, CRH, and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. CONCLUSION: Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

Prenatal vitamin C and E supplementation in smokers is associated with reduced placental abruption and preterm birth: a secondary analysis.

OBJECTIVE: Smoking and pre-eclampsia (PE) are associated with increases in preterm birth, placental abruption and low birthweight. We evaluated the relationship between prenatal vitamin C and E (C/E) supplementation and perinatal outcomes by maternal self-reported smoking status focusing on outcomes known to be impacted by maternal smoking. DESIGN/SETTING/POPULATION: A secondary analysis of a multi-centre trial of vitamin C/E supplementation starting at 9-16 weeks in low-risk nulliparous women with singleton gestations. METHODS: We examined the effect of vitamin C/E by smoking status at randomisation using the Breslow-Day test for interaction. MAIN OUTCOME MEASURES: The trial's primary outcomes were PE and a composite outcome of pregnancy-associated hypertension (PAH) with serious adverse outcomes. Perinatal outcomes included preterm birth and abruption. RESULTS: There were no differences in baseline characteristics within subgroups (smokers versus nonsmokers) by vitamin supplementation status. The effect of prenatal vitamin C/E on the risk of PE (P = 0.66) or PAH composite outcome (P = 0.86) did not differ by smoking status. Vitamin C/E was protective for placental abruption in smokers (relative risk [RR] 0.09; 95% CI 0.00-0.87], but not in nonsmokers (RR 0.92; 95% CI 0.52-1.62) (P = 0.01), and for preterm birth in smokers (RR 0.76; 95% CI 0.58-0.99) but not in nonsmokers (RR 1.03; 95% CI 0.90-1.17) (P = 0.046). CONCLUSION: In this cohort of women, smoking was not associated with a reduction in PE or the composite outcome of PAH. Vitamin C/E supplementation appears to be associated with a reduction in placental abruption and preterm birth among smokers.

Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?

OBJECTIVE: To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. DESIGN: A nested case-control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. SETTING: A multicentre study in 16 academic medical centres in the USA. POPULATION: Low-risk nulliparous women. METHODS: Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9-12, 15-18 and 23-26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. MAIN OUTCOME MEASURES: Change in PlGF, sFlt-1 and sEng. RESULTS: Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64-99), 77% (95% CI 50-93) and 77% (95% CI 50-93) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. CONCLUSION: Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Efficacy and side effect profile of varying doses of intrathecal fentanyl added to bupivacaine for labor analgesia.

The purpose of this randomized, double blinded and controlled study was to determine the optimal dose of intrathecal fentanyl when combined with bupivacaine 2.5 mg for initiation of labor analgesia. Parous parturients with cervical dilation between 3 and 5 cm were randomized to receive intrathecal fentanyl 0 (control), 5, 10, 15, 20 or 25 micrograms, combined with bupivacaine 2.5 mg, followed by a lidocaine/epinephrine epidural test dose. Visual analog pain scores (VAPS) and the presence of side effects were determined every 15 min until the parturient requested additional analgesia. Fetal heart rate (FHR) tracings were compared between groups. All parturients who received fentanyl >/= 15 micrograms had VAPS < 20 mm and duration of analgesia > 15 min, but this was not true for all parturients with fentanyl doses < 15 micrograms. Duration of analgesia was shorter for fentanyl groups 0, 5 and 10 micrograms, compared to groups 15, 20 and 25 micrograms, but there was no difference between the 15, 20 and 25 micrograms groups. There was no difference in the incidence of nausea and vomiting, or in FHR tracing changes. The incidence of pruritus was greater in all fentanyl groups compared to control. These data suggest that, when combined with intrathecal bupivacaine 2.5 mg, fentanyl 15 micrograms provides satisfactory analgesia to all parturients. Higher fentanyl doses produced no additional benefit in duration or quality of analgesia.

The dose-response of intrathecal sufentanil added to bupivacaine for labor analgesia.

BACKGROUND: Regional analgesia for labor often is initiated with an intrathecal injection of a local anesthetic and opioid. The purpose of this prospective, randomized, blinded study was to determine the optimal dose of intrathecal sufentanil when combined with 2.5 mg bupivacaine for labor analgesia. METHODS: One hundred seventy parous parturients with cervical dilation between 3-5 cm were randomized to receive intrathecal 0 (control), 2.5, 5.0, 7.5, or 10.0 microg sufentanil combined with 2.5 mg bupivacaine, followed by a lidocaine epidural test dose, for initiation of analgesia (34 patients in each group). Visual analog scores and the presence of nausea, vomiting, and pruritus were determined every 15 min until the patient requested additional analgesia. Fetal heart rate tracings were compared between groups. RESULTS: Groups were similar for age, height, weight, oxytocin dose, duration of labor, and baseline visual analog scores. Duration of action was significantly shorter for control patients (39 +/- 25 min [mean +/- SD]) compared with those administered sufentanil, all doses (93 +/- 32, 93 +/- 47, 94 +/- 33, 97 +/- 39 min), but was not different among groups administered 2.5, 5.0, 7.5, or 10.0 microg sufentanil. More patients who received 10 microg sufentanil reported nausea and vomiting than did control patients. The severity of pruritus increased with administration of 7.5 and 10.0 microg sufentanil. There was no difference in fetal heart rate changes among groups. CONCLUSIONS: Intrathecal bupivacaine (2.5 mg) without sufentanil did not provide satisfactory analgesia for parous patients. However, bupivacaine combined with 2.5 microg sufentanil provided analgesia comparable to higher doses, with a lower incidence of nausea and vomiting and less severe pruritus.

Cost-effectiveness of elective cesarean delivery after one prior low transverse cesarean.

OBJECTIVE: This analysis was undertaken to better understand the costs and health consequences of a trial of labor after cesarean when compared with a policy of routine elective repeat cesarean delivery. METHODS: A decision-tree model incorporating a Markov analysis was used to examine the reproductive life of a hypothetical cohort of 100,000 pregnant women whose only prior pregnancy was delivered through a low transverse cesarean incision. Using this model, the policy of performing routine elective cesarean delivery was compared with a policy of allowing a trial of labor. Main outcome measures were maternal and neonatal morbidity and mortality, total costs to the health care system, and cost per major neonatal complication avoided (death or permanent neurologic sequelae). RESULTS: The consequences of routine elective cesarean delivery for a second birth are significant, with an additional 117,748 cesarean deliveries, 5500 maternal morbid events, and $179 million incurred during the reproductive life of 100,000 women. The prevention of one major adverse neonatal outcome requires 1591 cesarean deliveries and $2.4 million. Sensitivity analysis confirms the robustness of the analysis. CONCLUSION: Routine elective cesarean for a second delivery for women with a prior low transverse cesarean incision results in an excess of maternal morbidity and mortality and a high cost to the medical system.

A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group.

OBJECTIVE: Treatment with heparin and low-dose aspirin improves fetal survival among women with antiphospholipid syndrome. Despite treatment, however, these pregnancies are frequently complicated by preeclampsia, fetal growth restriction, and placental insufficiency, often with the result of preterm birth. Small case series suggest that intravenous immune globulin may reduce the rates of these obstetric complications, but the efficacy of this treatment remains unproven. This pilot study was undertaken to determine the feasibility of a multicenter trial of intravenous immune globulin and to assess the impact on obstetric and neonatal outcomes among women with antiphospholipid syndrome of the addition of intravenous immune globulin to a heparin and low-dose aspirin regimen. STUDY DESIGN: This multicenter, randomized, double-blind pilot study compared treatment with heparin and low-dose aspirin plus intravenous immune globulin with heparin and low-dose aspirin plus placebo in a group of women who met strict criteria for antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a single live intrauterine fetus at

Tumor necrosis factor-alpha is decreased in the umbilical cord plasma of patients with severe preeclampsia.

We investigated the role of the fetal immune system in pregnancies complicated by preeclampsia by assessing umbilical cord plasma levels of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Nineteen nulliparous patients with severe preeclampsia composed the study group (group A). A comparison group was comprised of 19 healthy nulliparous patients with uneventful pregnancies (group B). Mixed umbilical cord blood was collected immediately after delivery. Plasma was prepared and all samples were assayed for TNF-alpha and IL-1beta by specific enzyme-linked immunoassays (ELISAs). Data are presented as the median with range of values. The length of labor was similar in both groups. TNF-alpha was detected less frequently in the umbilical cord plasma of preeclamptic patients than in the umbilical cord plasma of control patients (57.9 vs. 89.5%, p < 0.05), and the concentrations of TNF-alpha were significantly lower in the umbilical cord plasma of the preeclamptic patients [20 pg/ml (0-80 pg/mL) vs. 50 pg/mL (0-310 pg/mL), p < 0.05]. Umbilical cord plasma IL-1beta detection rates and concentrations from the preeclamptic and control patients were similar, [15.8 vs. 5.3%, 0 pg/mL (0-40 pg/mL) vs 0 pg/mL (0-10 pg/mL)]. The lower concentrations of TNF-alpha in umbilical cord plasma of patients with severe preeclampsia suggest that release of TNF-alpha by the fetus and mother are independent and may reflect adaptation of the fetus to reduced placental perfusion in preeclampsia.

Active management of labor.

The active management of labor may be one approach to achieving lower rates of intervention. Numerous institutions have reported lower CS rates since initiating this labor management scheme, and concurrent decreases in the length of labor and infectious morbidity have been demonstrated. Sufficient data now exist to conclude that such programs can be instituted without deleterious effects on neonatal outcomes. Nevertheless, success in decreasing CS rates has not been uniform and may be confined to certain settings. Other approaches to labor management may be as good or better at achieving low rates of intervention with minimum morbidity. Any approach that emphasizes advocacy for vaginal birth is likely to produce some success and should receive support.

Vaginal birth after cesarean: an appraisal of fetal risk.

OBJECTIVE: To expand on prior investigations and further evaluate the fetal risk associated with vaginal birth after cesarean (VBAC) by examining the incidence not only of a depressed Apgar score at 5 minutes but also of fetal acidemia. METHODS: Between January 1, 1991, and December 31, 1996, the following groups of patients who delivered a singleton fetus with birth weight greater than 750 g were identified: 2082 patients with one or more prior cesarean deliveries who were allowed a trial of labor, 1677 of whom delivered vaginally and 405 of whom delivered by repeat cesarean; 920 patients delivered by elective repeat cesarean; 22,863 patients without a prior cesarean who delivered vaginally; and 2432 patients delivered by primary cesarean after laboring. Umbilical cord arterial blood gases were obtained in 88.3% of these deliveries. Comparisons of Apgar scores at 5 minutes and umbilical cord arterial pH measurements were made between groups with chi2 or Fisher exact test, and odds ratios (ORs) were calculated. RESULTS: The only significant differences were noted between those patients who delivered vaginally after a prior cesarean and those patients who delivered vaginally without a prior cesarean. Neonates in the successful VBAC group were more likely to have an Apgar score at 5 minutes less than 7 (OR 1.52) or an umbilical arterial pH less than 7.1 (OR 1.69). Those neonates, however, were not at greater risk for an Apgar score less than 4 or a pH less than 7.0. CONCLUSION: Our experience suggests that VBAC poses a low level of fetal risk, although a much larger sample size would be required to exclude a two-fold increase in potentially damaging fetal acidemia.

Risk factors for cesarean delivery in twin gestations near term.

OBJECTIVE: We evaluated the risk factors associated with cesarean delivery in laboring twin gestations at least 36 completed weeks. METHODS: We reviewed the records of 134 women with twin gestations who underwent a trial of labor between 1993 and 1995. Women who delivered by cesarean were compared with women who delivered vaginally. The factors associated with an increased risk for cesarean were determined using univariate analysis. Logistic regression was used to determine which of those factors was most strongly associated with cesarean delivery. RESULTS: Of 134 laboring twin gestations, 25 (18.7%) delivered by cesarean and 109 (81.3%) delivered vaginally. Univariate analysis revealed that women who delivered by cesarean were more likely to be nulliparous, have a less advanced cervix at both admission and epidural placement, a higher mean oxytocin infusion rate for induction or augmentation of labor, a combined fetal weight greater than 5500 g, and received magnesium for seizure prophylaxis. Multivariate analysis identified that nulliparity and timing of epidural administration were the factors most strongly associated with cesarean delivery. CONCLUSION: The timing of epidural analgesia is a modifiable risk factor strongly associated with cesarean delivery in term and near-term laboring twin gestations.

Neonatal outcomes in triplet gestations after a trial of labor.

OBJECTIVE: This study aimed to compare neonatal outcomes in a cohort of triplet gestations undergoing a trial of labor with those of a similar cohort delivered by elective cesarean delivery. STUDY DESIGN: Thirty-three women with triplet gestations who underwent a trial of labor were compared with a matched cohort of 33 women with triplet gestations who were delivered of their infants by elective cesarean delivery. Neonatal outcomes assessed included respiratory distress syndrome, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, Apgar scores, and birth trauma. RESULTS: Twenty-nine of 33 women (87.9%) who underwent a trial of labor had a successful vaginal delivery of all 3 neonates. One patient was delivered of her first triplet vaginally but then required a cesarean delivery for abruptio placentae; 3 other patients were delivered of their infants by cesarean section for active-phase arrest of labor. There were no differences in neonatal outcomes between the 2 groups, although triplet neonates delivered by elective cesarean section demonstrated a trend toward a greater incidence of respiratory distress syndrome (P = .09). CONCLUSION: Our experience suggests that offering vaginal delivery is an acceptable management plan for triplet gestations.

Maternal hospital charges associated with trial of labor versus elective repeat cesarean section.

BACKGROUND: Although cesarean section is known to be associated with higher hospital charges than vaginal delivery, cost comparisons require further investigation. This study compared maternal hospital charges of women with one previous cesarean section undergoing a trial of labor with the charges of women who underwent an elective repeat cesarean section. Hospital charges for the trial of labor group were also compared with charges of women with a previous vaginal delivery but no previous cesarean section. METHODS: A retrospective analysis of three primiparous privately insured patient groups who gave birth from July 1992 to October 1993 was conducted. Hospital charges for 50 primiparas with previous cesarean births who underwent a trial of labor were compared with those of 50 contemporaneous primiparas who underwent elective repeat cesarean section, and with those of 50 primiparas without a past history of cesarean birth. RESULTS: Trial of labor was associated with a mean maternal hospital charge of $5820 +/- $1609 compared with $6785 +/- $771 for elective repeat cesarean section (p < 0.001). Trial of labor was also associated with a decreased length of stay when compared with elective cesarean section (2.48 +/- 0.88 days vs 3.62 +/- 0.57 days, p < 0.001). The difference in charges between these two groups was primarily due to charges associated with length of stay and the operating room, but was partly offset by charges associated with labor. The group of women without a past history of cesarean birth had a mean maternal hospital charge of $4685 +/- $966 and a mean length of stay of 1.96 +/- 0.63 days. CONCLUSIONS: Trial of labor is associated with an overall 14 percent reduction in maternal hospital charges and a 31 percent reduction in length of stay compared with elective repeat cesarean section.

Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial.

OBJECTIVE: Our aim was to determine whether the presence of fetal fibronectin in vaginal secretions of patients with symptoms suggestive of preterm labor predicts preterm delivery. STUDY DESIGN: Patients who were examined at the hospital between 24 weeks' and 34 weeks 6 days' gestation with intact membranes, no prior tocolysis, symptoms suggestive of preterm labor, and cervical dilation < 3 cm were recruited at 10 sites. Swabs of the posterior fornix were assayed for the presence of fetal fibronectin by monoclonal antibody assay, with a positive result defined as > or = 50 ng/ml. Results were not available to the managing physicians. Tocolysis was used when clinically indicated after specimen collection. RESULTS: A total of 763 patients had fetal fibronectin results and pregnancy outcome data available for analysis. Fetal fibronectin was detected in specimens from 150 (20%) patients. Compared with patients who had negative results, patients who had positive results for fetal fibronectin were more likely to be delivered within 7 days (relative risk 25.9 [95% confidence interval 7.8 to 86]), within 14 days (relative risk 20.4 [95% confidence interval 8.0 to 53]), and before 37 completed weeks (relative risk 2.9 [95% confidence interval 2.2 to 3.7]). The negative predictive values for delivery within 7 days, within 14 days, and at < 37 weeks were 99.5%, 99.2%, and 84.5%, respectively. When we used multiple logistic regression analysis to control for potential confounding variables among singleton pregnancies, only the presence of fetal fibronectin (odds ratio 48.8, 95% confidence interval 7.4 to 320), prior preterm birth (odds ratio 8.3, 95% confidence interval 1.5 to 46.6), and tocolysis (odds ratio 4.1, 95% confidence interval 1.0 to 16.0) were associated with birth within 7 days; fetal fibronectin (odds ratio 3.6, 95% confidence interval 2.2 to 5.9), prior preterm birth (odds ratio 2.5, 95% confidence interval 1.4 to 4.4), cervical dilatation > 1 cm (odds ratio 2.9, 95% confidence interval 1.6 to 5.2), and tocolysis (odds ratio 4.5, 95% confidence interval 2.8 to 7.2) were all independently associated with delivery before 37 weeks. CONCLUSION: In a population of patients with symptoms, the presence of fetal fibronectin in vaginal secretions best defines a subgroup at increased risk for delivery within 7 days; the high negative predictive value of fetal fibronectin sampling supports less intervention for patients with this result.

Soluble tumor necrosis factor receptors and interleukin-6 levels in patients with severe preeclampsia.

OBJECTIVE: To investigate whether serum and amniotic fluid (AF) levels of soluble tumor necrosis factor receptors and interleukin-6, markers of immune activation and endothelial dysfunction, are altered in patients with severe preeclampsia. METHODS: Plasma was collected before induction of labor, at delivery, and postpartum from 19 patients with severe preeclampsia. Amniotic fluid was also obtained in early labor from these patients. Similar samples were obtained from an antepartum control group matched for gestational age and a term control group without preeclampsia. All plasma and AF samples were assayed for p55 and p75 soluble tumor necrosis factor receptors and for interleukin-6 by specific enzyme-linked immunoassays. Levels in preeclamptic patients and the control groups were compared. RESULTS: Levels of both receptors were significantly elevated in AF and all maternal plasma samples except those collected 24 hours postpartum for patients with preeclampsia relative to levels in controls. Interleukin-6 was detected more frequently and in higher concentrations in the plasma collected before labor for preeclamptic patients compared with controls, but no difference was noted in interleukin-6 detection rates or plasma concentrations at delivery. Conversely, AF concentrations of interleukin-6 were significantly reduced in patients with preeclampsia. CONCLUSION: The increased levels of soluble tumor necrosis factor receptors found in patients with severe preeclampsia may represent a protective response to increased tumor necrosis factor activity and be a marker for immune activation. Increased interleukin-6 concentrations in maternal plasma before labor suggest the involvement of this cytokine as well in the altered immune response and its contribution to endothelial cell dysfunction.

Active management of labor.

Active management of labor was first instituted as a program to shorten the length of nulliparous labor. Numerous institutions have found that implementation of this program decreased rates of cesarean section. Two randomized trials have evaluated this program, with both showing that labor was shortened by approximately 2 hours and maternal infectious morbidity was decreased by approximately 50%. Although one trial demonstrated a significant reduction in the rate of cesarean birth, the other did not. No users have reported any increase in neonatal morbidity. For some institutions implementation of active management of labor principles may be one approach to decrease operative deliveries for dystocia.