Thomas Schmitz

Manual rotation in occiput posterior or transverse positions: risk factors and consequences on the cesarean delivery rate.

OBJECTIVE: To identify the risk factors for failure of manual rotation in patients with occiput posterior or transverse positions during labor and to study the cesarean rate according to the success of the rotation. METHODS: Case-control study comparing failure and success of manual rotation. Cases were all fetuses for whom rotation failed. We used computerized randomization (without matching) to select one control with a successful rotation during the same period for each case with a failed rotation. Maternal, neonatal, and obstetric risk factors for failed rotation were studied with bivariable and multivariable analyses. Mode of delivery was analyzed according to success of the rotation. RESULTS: During the study period, manual rotations were performed in 796 patients. The procedure failed in 77 (9.7%) women. Attempted rotation before full dilatation tripled the risk of failure in comparison with rotation at full dilatation (adjusted odds ratio 3.4, 95% confidence interval 1.3–8.6), and rotation for failure to progress quadrupled that risk in comparison with prophylactic rotation (adjusted odds ratio 3.3, 95% confidence interval 1.2–8.5). Failure of manual rotation was associated with a higher cesarean delivery rate than was success (58.8% compared with 3.8%, P<.001). All women with unsuccessful manual rotations who delivered vaginally delivered in the occiput posterior position, and all women with successful manual rotation delivering vaginally delivered in the occiput anterior position. CONCLUSION: Manual rotation may be an effective technique for reducing the cesarean delivery rate in patients with an occiput posterior or transverse position during labor. The success or failure of attempted manual rotation depends upon obstetric conditions, including the indication for rotation and cervical dilatation. LEVEL OF EVIDENCE: II

Improving continuous wound infusion effectiveness for postoperative analgesia after cesarean delivery: a randomized controlled trial.

OBJECTIVE: To evaluate in which anatomical layer (above the fascia or below the fascia) continuous wound infusion of local anesthetic, combined with nonsteroidal antiinflammatory drugs, through a multiorifice catheter has the best effectiveness during the first 48 hours on postoperative pain intensity after elective cesarean delivery. METHODS: Fifty-six women undergoing elective cesarean delivery under spinal anesthesia were randomly allocated to receive 48-hour continuous wound infusion either above the fascia or below the fascia using ropivacaine and ketoprofene through a multiholed wound catheter. No other systemic analgesics were used, except for rescue patient-controlled intravenous morphine. Evaluation by a blinded investigator included visual analog scale scores at rest and at movement, morphine consumption, patient satisfaction, residual pain at 1 and 6 months, and undesirable side effects. RESULTS: Continuous wound infusion below the fascia resulted in significantly reduced pain at rest and total postoperative morphine consumption (15.7 mg, 95% confidence interval 9.7–20.7 mg) compared with wound administration above the fascia (26.4 mg, 95% confidence interval 18.1–34.7). No undesirable side effects or residual pain requiring treatment were recorded in both groups, whereas analgesia and satisfaction were excellent. CONCLUSION: After cesarean delivery, continuous wound infusion over 48 hours with ropivacaine and ketoprofene through a multiholed wound catheter inserted below the fascia results in better analgesia when compared with administration above the fascia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01160913. LEVEL OF EVIDENCE: I

Maternal Immune Response and Neonatal Seroprotection From a Single Dose of a Monovalent Nonadjuvanted 2009 Influenza A(H1N1) Vaccine: A Single-Group Trial

BACKGROUNDnPregnant women and infants who get influenza are at increased risk for severe illness.nnnOBJECTIVEnTo evaluate the immunogenicity and transplacental antibody transfer of 2009 pandemic influenza A(H1N1) vaccine administered during pregnancy.nnnDESIGNnProspective, multicenter, single-group clinical trial. (ClinicalTrials.gov registration number: NCT01024400)nnnSETTINGnFive level-3 perinatal centers in France.nnnPATIENTSn107 pregnant women between 22(0/7) and 32(0/7) weeks of gestation.nnnINTERVENTIONnAn intramuscular dose of a nonadjuvanted H1N1 vaccine that contained 15 mcg of hemagglutinin.nnnMEASUREMENTSnProportion of women with an influenza antibody titer of 1:40 or greater at days 21 and 42 after vaccination, delivery, and 3 months after delivery. Seroconversion rate, fold increase in the geometric mean titer 21 days after vaccination, and proportion of neonates with an antibody titer of 1:40 or greater at birth were also assessed.nnnRESULTSnAt baseline, 19% of the women had an antibody titer of 1:40 or greater. At day 21, 98% of the women had an antibody titer of 1:40 or greater, the seroconversion rate was 93%, and the fold increase in geometric mean titer was 67.4. At day 42, delivery, and 3 months after delivery, 98%, 92%, and 90% of the women, respectively, had an antibody titer of 1:40 or greater. Ninety-five percent of the cord serum samples obtained from 88 neonates showed an antibody titer of 1:40 or greater. The median neonate-mother antibody titer ratio was 1.4.nnnLIMITATIONSnOnly healthy pregnant women were selected. Data on hemagglutination inhibition antibody titers of infants were reported only at birth.nnnCONCLUSIONnA single dose of a nonadjuvanted influenza A(H1N1) vaccine with 15 mcg of hemagglutinin triggered a strong immune response in pregnant women and a high rate of neonatal seroprotection.nnnPRIMARY FUNDING SOURCEnFrench National Institute of Health and Medical Research.

Manual Rotation in Occiput Posterior or Transverse Positions; Risk Factors and Consequences on the Cesarean Delivery Rate

Occiput posterior and transverse positions make up about one-fifth of all positions when labor begins and 5% at the time of delivery. These malpositions are accepted risk factors for a longer second stage of labor, instrumental and cesarean deliveries, and severe perineal lacerations. Manual rotation of the fetal head is sometimes used in an effort to reduce the need for cesarean delivery, but data on its success rate and safety are limited. This retrospective case-control study attempted to identify obstetrical conditions prevailing at the time rotation is attempted that help to predict its success or failure. Manual rotation was carried out in 796 patients during the study, and failed in 77 instances, 9.7% of the total. Rotation was performed only when dilatation reached 7 cm. One hundred forty-seven files (18% of all rotations) were analyzed, of which 68 were failed rotations and 79 were successful. On multivariable analysis, attempting rotation before full dilation approximately tripled the risk of failure (adjusted odds ratio [OR], 3.4; 95% confidence interval [CI], 1.3-8.6). Rotation done after failure to progress in labor increased the risk of failure compared with prophylactic rotation (adjusted OR, 3.3; 95% CI, 1.2-8.5). The cesarean delivery rate was markedly higher when manual rotation failed than when it succeeded (58.8% vs. 3.8%; P < 0.001). Success rates were similar for the occiput transverse and occiput posterior positions. All women who delivered vaginally after successful manual rotation delivered in the occiput anterior position, while those who delivered vaginally after failed manual rotation delivered in the occiput posterior position. Cervical lacerations occurred in only 2 patients, in whom manual rotation succeeded, but not in any of the failed cases. No woman in this study had a fourth-degree perineal laceration, but there were 2 third-degree lacerations in the failure group and 1 in the success group. The episiotomy rate was 44%. The incidence of severe fetal heart rate abnormalities during attempted manual rotation was 9.9%, and there were mild to moderate abnormalities in 19%; they did not appear to be associated with cesarean delivery.

PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation.

The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-α, IL-1β, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NFκB, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the glycogen-trophoblastic cells of the placenta. This activation was disrupted by PDE4 inhibition, and inflammation-induced preterm delivery and fetal demise were prevented. PDE4 selective inhibitors may thus represent a novel effective treatment to delay inflammation-induced preterm delivery and to prevent adverse outcomes in infants.

Maternal markers for detecting early-onset neonatal infection and chorioamnionitis in cases of premature rupture of membranes at or after 34 weeks of gestation: a two-center prospective study

BackgroundAccurate prediction of infection, including maternal chorioamnionitis and early-onset neonatal infection, remains a critical challenge in cases of preterm rupture of membranes and may influence obstetrical management. The aim of our study was to investigate the predictive value for early-onset neonatal infection and maternal histological and clinical chorioamnionitis of maternal biological markers in routine use at or after 34 weeks of gestation in women with premature rupture of membranes.MethodsWe conducted a two-center prospective study of all women admitted for premature rupture of membranes at or after 34 weeks of gestation. The association of C-reactive protein, white blood cell count, vaginal sample bacteriological results, and a prediction model at admission, for early-onset neonatal infection and maternal chorioamnionitis were analyzed by comparing areas under the receiver operating characteristic curves and specificity.ResultsThe study included 399 women. In all, 4.3% of the newborns had an early-onset neonatal infection and 5.3% of the women had clinical chorioamnionitis. Histological chorioamnionitis was detected on 10.8% of 297 placentas tested. White blood cell counts and C-reactive protein concentrations were significantly associated with early-onset neonatal infection and included in a prediction model. The area under the receiver operating characteristic curve of this model was 0.82 (95% CI [0.72, 0.92]) and of C-reactive protein, 0.80 (95% CI [0.68, 0.92]) (p = 1.0). Specificity was significantly higher for C-reactive protein than for the prediction model (48% and 43% respectively, p < 0.05). C-reactive protein was associated with clinical and histological chorioamnionitis, with areas under the receiver operating characteristic curve of 0.61 (95% CI [0.48, 0.74]) and 0.62 (95% CI [0.47, 0.74]), respectively.ConclusionsThe concentration of C-reactive protein at admission for premature rupture of membranes is the most accurate infectious marker for prediction of early-onset neonatal infection in routine use with a sensitivity > 90%. A useful next step would be a randomized prospective study of management strategy comparing CRP at admission with active management to assess whether this more individualized care is a safe alternative strategy in women with premature rupture of membranes at or after 34 weeks.

The PDE4 inhibitor rolipram prevents NF-kappaB binding activity and proinflammatory cytokine release in human chorionic cells

Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-α when stimulated by LPS. The transcription factor NF-κB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-α. LPS induces the nuclear translocation of the NF-κB p65 subunit and the activation of three different NF-κB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-α production and the activation of the three NF-κB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.

Inflammation of Choriodecidua Induces Tumor Necrosis Factor Alpha-Mediated Apoptosis of Human Myometrial Cells

Abstract The present study investigated the ability of human choriodecidua to induce myometrial cell apoptosis through the secretion of tumor necrosis factor alpha (TNF). The secretion of TNF was evaluated in the culture supernatants of amnion and choriodecidua explants that were exposed to the bacterial endotoxin lipopolysaccharide (LPS) to mimic inflammation. The choriodecidua explants produced more TNF than the amnion explants in response to LPS stimulation, despite the fact that the choriodecidua had lower levels of TLR4 expression. Moreover, conditioned medium obtained from LPS-treated choriodecidua explants, but not that from amnion explants, decreased the number of viable cultured myometrial cells and induced cell apoptosis by inducing the overexpression of the proapoptotic protein BAX and by decreasing the expression of the anti-apoptotic protein BCL2. Neutralization of TNF in the choriodecidua-conditioned medium reversed this effect. Exogenous TNF mimicked LPS-treated choriodecidua-conditioned medium in that it induced myometrial cell apoptosis, reduced BCL2 expression, and increased BAX expression. Using neutralizing antibodies against both subtypes of TNF receptors, we found that only TNFRSF1A participates in TNF-induced myometrial cell apoptosis. Our in vitro model of LPS-induced inflammation of human fetal membrane explants suggests a mechanism by which TNF secreted by choriodecidua governs human myometrial cell apoptosis at the end of pregnancy. These data support the hypothesis that TNF participates in the complex network of signaling processes associated with uterine involution.

Prostaglandin E2 Analogue Sulprostone for Treatment of Atonic Postpartum Hemorrhage

OBJECTIVES: Use of prostaglandins, including sulprostone (an E2 analog), is recommended for second-line uterotonic treatment of atonic postpartum hemorrhage and might be considered as an indicator of quality of care in severe atonic postpartum hemorrhage management. Our objective was to estimate whether sulprostone was appropriately used and how it was tolerated in women with atonic postpartum hemorrhage. METHODS: This large population-based study (146,781 deliveries) included 4,038 women with clinically assessed atonic postpartum hemorrhage in 106 French hospitals during 1 year. Severe postpartum hemorrhage was defined as one of the following: hemoglobin decline of 4 g/dL or more, transfusion, arterial embolization, surgical procedures, transfer to intensive care unit, or death. Sulprostone use in severe atonic postpartum hemorrhage was analyzed according to the mode of delivery and the characteristics of the maternity units. RESULTS: Rates of sulprostone use were only 33.9% (n=1,370) and 53.5% (n=657) among women with atonic (n=4,038) and severe atonic (n=1,227) postpartum hemorrhage, respectively. In the latter population, sulprostone administration was less frequent after vaginal delivery than after cesarean delivery (45.6% compared with 86.5%, P<.01) in units performing fewer than 1,500 annual deliveries in public nonuniversity hospitals and in units where the obstetrician or anesthesiologist was not present 24 hours per day, 7 days per week. Fifty-one of the 1,370 women with sulprostone-treated atonic postpartum hemorrhage (3.7%, 95% confidence interval [CI] 2.7–4.7) experienced side effects, including seven (0.5%, 95% CI 0.2–1.0) with severe cardiovascular or respiratory symptoms that resolved when the hypovolemic shock was corrected and drug administration was stopped. CONCLUSION: Sulprostone is underused for treating severe atonic postpartum hemorrhage after vaginal delivery, despite low rates of severe side effects in this population-based study. LEVEL OF EVIDENCE: III

PDE4 as a target in preterm labour

Cyclic nucleotide phosphodiesterases (PDE) are the enzymes catalyzing the hydrolysis and inactivation of the second messengers, cAMP and cGMP. Eleven PDE families are described to date, and selective inhibitors of some PDEs families are currently used in clinic for treating cardiovascular disorders, erectile dysfunction, and pulmonary hypertension. Isoforms of the PDE4 family are involved in smooth muscle contraction and inflammation. PDE4 selective inhibitors are currently in clinical trials for the treatment of diseases related to inflammatory disorders. Because of their myorelaxant properties, we first examined their expression in human myometrium and uncover an increased expression of one specific isoform, PDE4B2, in the near-term myometrium as compared to myometrium in the nonpregnant state. Using human myometrial cells in culture, we demonstrated that PDE4B2 can be induced by its own substrate, under the control of one of the major utero-contractile agonists, PGE2, itself upregulated by the proinflammatory cytokine IL-1β. Functionally, augmentation of global PDE4 activity decreases the ability of β-adrenergic agonists (the most commonly used tocolytic drugs) to inhibit myometrial contraction at the end of pregnancy and during pathophysiological situations, such as persistent intrauterine inflammation which is a major cause of very preterm delivery. Currently exploring the anti-inflammatory properties of PDE4 inhibitors in gestational tissues, we recently demonstrated the ability of these drugs to block a persistent inflammatory response of the foetal membranes in Humans and to prevent inflammation-driven preterm delivery and foetal demise in mice. These data open up a new therapeutical strategy to prevent inflammation-induced preterm delivery and its sequelae in very preterm infants.