Methods for the induction of labor: efficacy and safety.

This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 µg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.

Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines.

BACKGROUND: Investigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production. METHODS: This study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12-20 weeks gestation) and after supplementation (34-36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis. RESULTS: We enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations. CONCLUSIONS: Prenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations. TRIAL REGISTRATION: Clinical Trial Registration: registration number NCT00711971 7/7/2008.

A Comparison of Methods for the Diagnosis of Fetal Growth Restriction Between the Royal College of Obstetricians and Gynaecologists and the American College of Obstetricians and Gynecologists.

OBJECTIVE: The Royal College of Obstetricians and Gynaecologists (RCOG) defines fetal growth restriction as ultrasound-estimated fetal weight less than the 10th percentile or abdominal circumference less than the 10th percentile; the American College of Obstetricians and Gynecologists (ACOG) defines fetal growth restriction as estimated fetal weight less than the 10th percentile alone. We compared each method's ability to predict small for gestational age (SGA) at birth. METHODS: For this retrospective study of diagnostic accuracy, we reviewed deliveries at the University of New Mexico Hospital from January 1, 2013, to March 31, 2017. We included mothers with singleton, well-dated pregnancies and nonanomalous fetuses undergoing indicated fetal growth restriction surveillance with an ultrasound-estimated fetal weight within 30 days of delivery. Estimated fetal weights and percentiles were calculated using the Hadlock intrauterine growth curve. Small for gestational age was defined as birth weight less than the 10th percentile based on a recent, sex-specific curve. We calculated the area under the curve, sensitivity, specificity, and positive and negative likelihood ratios for various approaches using abdominal circumference and estimated fetal weight to diagnose fetal growth restriction, including the definitions endorsed by ACOG and RCOG. RESULTS: We included 1,704 pregnancies with a mean ultrasonography-to-delivery interval of 14.0 days (±8.6). There were 235 SGA neonates (13.8%). The rate of fetal growth restriction was 13.6% when using ACOG's criteria and 16.9% according to RCOG's criteria (P=.007). The area under the curve of RCOG's diagnostic approach was 0.78 (95% CI 0.76-0.80), which was higher than ACOG's (0.76, 95% CI 0.74-0.78, P=.01). Sensitivities and specificities of the various methods were similar. Adopting estimated fetal weight or abdominal circumference less than the 10th percentile instead of estimated fetal weight alone to predict SGA at birth would correctly identify one additional case of SGA for each 14 patients assessed. CONCLUSION: The diagnostic approach endorsed by RCOG is a marginally better predictor of SGA at birth compared with the method endorsed by ACOG. Future research should consider the potential benefits and harms of the different methods in different populations.

Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial.

BACKGROUND: Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. OBJECTIVE: Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. STUDY DESIGN: At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure ≥160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure ≥150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. RESULTS: We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, body mass index, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen vs acetaminophen groups (35.3 vs 38.0 hours, P = .30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure ≥150/100 mm Hg, postpartum mean arterial pressure, maximum postpartum systolic or diastolic blood pressures, any postpartum blood pressure ≥160/110 mm Hg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.4 hours and ibuprofen group was 56.7 hours (P = .26). At 6 weeks postpartum, there were no differences between groups in the rates of obstetric triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. CONCLUSION: The first-line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features.

Pathway Markers for Pro-resolving Lipid Mediators in Maternal and Umbilical Cord Blood: A Secondary Analysis of the Mothers, Omega-3, and Mental Health Study.

The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are precursors to immune regulatory and specialized pro-resolving mediators (SPM) of inflammation termed resolvins, maresins, and protectins. Evidence for lipid mediator formation in vivo can be gained through evaluation of their 5-lipoxygenase (LOX) and 15-LOX metabolic pathway precursors and downstream metabolites. We performed a secondary blood sample analysis from 60 participants in the Mothers, Omega-3, and Mental Health study to determine whether SPM and SPM precursors are augmented by dietary EPA- and DHA-rich fish oil supplementation compared to soy oil placebo. We also aimed to study whether SPM and their precursors differ in early and late pregnancy or between maternal and umbilical cord blood. We found that compared to placebo supplementation, EPA- and DHA-rich fish oil supplementation increased SPM precursor 17-hydroxy docosahexaenoic acid (17-HDHA) concentrations in maternal and umbilical cord blood (P = 0.02). We found that the D-series resolvin pathway marker 17-HDHA increased significantly between enrollment and late pregnancy (P = 0.049). Levels of both 14-HDHA, a maresin pathway marker, and 17-HDHA were significantly greater in umbilical cord blood than in maternal blood (P < 0.001, both).

Vitamin D levels and perinatal depressive symptoms in women at risk: a secondary analysis of the mothers, omega-3, and mental health study.

BACKGROUND: Vitamin D insufficiency may be associated with depressive symptoms in non-pregnant adults. We performed this study to evaluate whether low maternal vitamin D levels are associated with depressive symptoms in pregnancy. METHODS: This study was a secondary analysis of a randomized trial designed to assess whether prenatal omega-3 fatty acid supplementation would prevent depressive symptoms. Pregnant women from Michigan who were at risk for depression based on Edinburgh Postnatal Depression Scale Score or history of depression were enrolled. Participants completed the Beck Depression Inventory (BDI) and Mini International Neuropsychiatric Interview at 12-20 weeks, 26-28 weeks, 34-36 weeks, and 6-8 weeks postpartum. Vitamin D levels were measured at 12-20 weeks (N = 117) and 34-36 weeks (N = 112). Complete datasets were available on 105 subjects. Using regression analyses, we evaluated the relationship between vitamin D levels with BDI scores as well as with MINI diagnoses of major depressive disorder and generalized anxiety disorder. Our primary outcome measure was the association of maternal vitamin D levels with BDI scores during early and late pregnancy and postpartum. RESULTS: We found that vitamin D levels at 12-20 weeks were inversely associated with BDI scores both at 12-20 and at 34-36 weeks' gestation (P < 0.05, both). For every one unit increase in vitamin D in early pregnancy, the average decrease in the mean BDI score was .14 units. Vitamin D levels were not associated with diagnoses of major depressive disorder or generalized anxiety disorder. CONCLUSIONS: In women at risk for depression, early pregnancy low vitamin D levels are associated with higher depressive symptom scores in early and late pregnancy. Future investigations should study whether vitamin D supplementation in early pregnancy may prevent perinatal depressive symptoms. TRIAL REGISTRATION: https://clinicaltrials.gov/ REGISTRATION NUMBER: NCT00711971.

Risk of postpartum hemorrhage among Native American women.

OBJECTIVE: To assess whether Native American women have an increased risk of postpartum hemorrhage (PPH) after vaginal delivery. METHODS: In a retrospective study, medical charts were reviewed for patients who delivered vaginally at Rehoboth McKinley Hospital in Gallup, NM, USA, between June 1, 2009, and June 30, 2012. Ethnic origin had been determined by self-report. PPH was defined as a visually estimated blood loss of more than 500 mL. Multivariable logistic analysis was undertaken to identify factors independently associated with PPH. RESULTS: Among 1062 eligible patients, 751 (70.7%) were Native American and 311 (29.3%) were non-native (white, African American, or Hispanic). A significantly higher proportion of Native Americans than non-native women developed PPH (87 [11.6%] vs 22 [7.0%]; P=0.02). In multivariable analysis, Native American ethnic origin was an independent predictor of PPH (odds ratio 1.8, 95% confidence interval 1.1-3.0; P=0.02). In a comparison with white women only, PPH was significantly more frequent among Native American women (87/751 [11.6%] vs 13/194 [6.7%]; P=0.01). CONCLUSION: Native American women have a higher risk of PPH after vaginal delivery than do non-native women.

Buprenorphine and methadone for opioid addiction during pregnancy.

Buprenorphine and methadone are opioid-receptor agonists used as opioid substitution therapy during pregnancy to limit exposure of the fetus to cycles of opioid withdrawal and reduce the risk of infectious comorbidities of illicit opioid use. As part of a comprehensive care plan, such therapy may result in improved access to prenatal care, reduced illicit drug use, reduced exposure to infections associated with intravenous drug use, and improved maternal nutrition and infant birth weight. This article describes differences in patient selection between the two drugs, their relative safety during pregnancy, and changes in daily doses as a guide for prescribing clinicians.

The Mothers, Omega-3, and Mental Health Study: a double-blind, randomized controlled trial.

OBJECTIVES: Maternal deficiency of the omega-3 fatty acid, docosahexaenoic acid (DHA), has been associated with perinatal depression, but there is evidence that supplementation with eicosapentaenoic acid (EPA) may be more effective than DHA in treating depressive symptoms. This trial tested the relative effects of EPA- and DHA-rich fish oils on prevention of depressive symptoms among pregnant women at an increased risk of depression. STUDY DESIGN: We enrolled 126 pregnant women at risk for depression (Edinburgh Postnatal Depression Scale score 9-19 or a history of depression) in early pregnancy and randomly assigned them to receive EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA), or soy oil placebo. Subjects completed the Beck Depression Inventory (BDI) and Mini-International Neuropsychiatric Interview at enrollment, 26-28 weeks, 34-36 weeks, and at 6-8 weeks' postpartum. Serum fatty acids were analyzed at entry and at 34-36 weeks' gestation. RESULTS: One hundred eighteen women completed the trial. There were no differences between groups in BDI scores or other depression endpoints at any of the 3 time points after supplementation. The EPA- and DHA-rich fish oil groups exhibited significantly increased postsupplementation concentrations of serum EPA and serum DHA respectively. Serum DHA- concentrations at 34-36 weeks were inversely related to BDI scores in late pregnancy. CONCLUSION: EPA-rich fish oil and DHA-rich fish oil supplementation did not prevent depressive symptoms during pregnancy or postpartum.

Total Serum Fatty Acid Analysis by GC-MS: Assay Validation and Serum Sample Stability.

Analysis of n3 fatty acids in serum samples has clinical applications in supplementation trials, but the analysis can be challenging due to low levels, stability issues and intra-individual variation. This study presents the single laboratory validation of a gas chromatographic-mass spectral (GC-MS) assay for analysis of fatty acid methyl esters (FAME) using sensitive single ion monitoring and provides data on fatty acid stability under different sample handling conditions. Recovery of total fatty acids from serum with Folch extraction was optimized and parallelism tests with spiked samples indicated that the serum matrix did not interfere with mass spectral quantitation. Precision and accuracy of the assay at the lowest limit of quantitation and at low, medium and high levels met with accepted guidelines for single laboratory validation. Several storage conditions that can be encountered with clinical samples also were evaluated for impact on fatty acid levels in serum. Serum from blood that was stored refrigerated for 3 days yielded similar results as serum that was prepared and frozen at -80°C immediately. Serum storage at room temperature for 3-24 hours and serum subjected to one freeze/thaw cycle had minimal effects on fatty acid levels. The intra-individual variability in pregnant women was reasonably small, with significant correlation coefficients ranging from 0.35 to 0.76 for blood drawn between 12-20 weeks versus 34-36 weeks of gestation. These results indicate that GC-MS with single ion monitoring is valid for the analysis of total fatty acids in clinical samples, even when blood processing cannot be performed in a timely manner.

Omega-3 fatty acids and pregnancy: current implications for practice.

PURPOSE OF REVIEW: We conducted this review to evaluate the evidence for maternal supplementation with omega-3 fatty acids during pregnancy for the prevention or treatment of common complications of pregnancy including preterm birth, pregnancy-induced hypertension and preeclampsia, as well as perinatal depression. We also evaluated the evidence supporting maternal omega-3 fatty acid supplementation to optimize infant neurocognitive development and for primary prevention of allergic diseases in childhood. RECENT FINDINGS: Omega-3 fatty acids through diet or dietary supplementation may reduce the risk for early preterm birth. Preliminary findings from small randomized controlled trials suggest that maternal omega-3 fatty acid supplementation during pregnancy may reduce the risk for allergic disease in childhood, but this observation requires confirmation by large appropriately powered randomized controlled trials. More research is needed before routine maternal supplementation for this indication can be recommended. SUMMARY: Although it is biologically plausible that maternal omega-3 fatty acid supplementation might prevent a number of pregnancy complications and optimize child health and development, indications for supplementation other than prevention of preterm births are currently investigational.

Methods of induction of labour: a systematic review.

BACKGROUND: Rates of labour induction are increasing. We conducted this systematic review to assess the evidence supporting use of each method of labour induction. METHODS: We listed methods of labour induction then reviewed the evidence supporting each. We searched MEDLINE and the Cochrane Library between 1980 and November 2010 using multiple terms and combinations, including labor, induced/or induction of labor, prostaglandin or prostaglandins, misoprostol, Cytotec, 16,16,-dimethylprostaglandin E2 or E2, dinoprostone; Prepidil, Cervidil, Dinoprost, Carboprost or hemabate; prostin, oxytocin, misoprostol, membrane sweeping or membrane stripping, amniotomy, balloon catheter or Foley catheter, hygroscopic dilators, laminaria, dilapan, saline injection, nipple stimulation, intercourse, acupuncture, castor oil, herbs. We performed a best evidence review of the literature supporting each method. We identified 2048 abstracts and reviewed 283 full text articles. We preferentially included high quality systematic reviews or large randomised trials. Where no such studies existed, we included the best evidence available from smaller randomised or quasi-randomised trials. RESULTS: We included 46 full text articles. We assigned a quality rating to each included article and a strength of evidence rating to each body of literature. Prostaglandin E2 (PGE2) and vaginal misoprostol were more effective than oxytocin in bringing about vaginal delivery within 24 hours but were associated with more uterine hyperstimulation. Mechanical methods reduced uterine hyperstimulation compared with PGE2 and misoprostol, but increased maternal and neonatal infectious morbidity compared with other methods. Membrane sweeping reduced post-term gestations. Most included studies were too small to evaluate risk for rare adverse outcomes. CONCLUSIONS: Research is needed to determine benefits and harms of many induction methods.

Meta-analysis of heterogeneous clinical trials: an empirical example.

Meta-analysis of heterogeneous clinical trials is currently sub-optimal. This is because there has been no improvement in the method of weighted averaging for such studies since the DL method in 1986. This article presents the argument for the use of situation specific weights to integrate results from such trials. An empirical example is given with data from a meta-analysis done 10 years earlier. Previously reported data on 21 studies that looked at the effect of working conditions on preterm births were re-analyzed. Several methods were used to estimate the overall effect sizes. Study specific scores were included in the weighting process when combining studies and it was shown that this model not only was more conservative than the model of DL but also retains the legitimacy of the pooled effect size. The inclusion of appropriate study specific scores in an appropriate meta-analysis model permits the quantification of the variation between studies based on something tangible as opposed to the random adjustments made by the random effects model to the pooled effect size. It is important that such differences are recognized by the wider research community so that meta-analyses remain a valid tool for synthesizing research.

Willingness or unwillingness to perform cesarean section for impending preterm delivery at 24 weeks' gestation: a cost-effectiveness analysis.

OBJECTIVE: This study was undertaken to compare the costs and health outcomes of 2 management options when encountering a 24-week gestation in labor. STUDY DESIGN: We constructed a decision model for willingness versus unwillingness to perform cesarean section for fetal indication (aggressive vs nonaggressive management). We modeled chance nodes for stillbirth, neonatal death, and long-term survival, with and without major morbidity. Main outcome measures were intact (healthy) infant and live infant. Cost-effectiveness analysis was conducted from a societal perspective to determine the cost-effectiveness of the 2 strategies. RESULTS: The probabilities of both intact survival (16.8% vs 12.9%) and survival with major morbidity (39.2% vs 19.4%) were higher with willingness to perform cesarean section. Nonaggressive management was less costly for delivery at 24 weeks' gestation. Aggressive management strategy would cost dollar 4,680,387 more than nonaggressive management for each additional intact infant, and dollar 766,241 more per additional live infant. CONCLUSION: Although the probability of survival is increased by physician willingness to perform cesarean section, the more cost-effective strategy is unwillingness because of a strong relationship to the increased probability of survival with major morbidity when physicians are willing to perform cesarean section for fetal indications.