Setting Of Preterm Premature Rupture Of Membranes Research Articles

Azithromycin dosing and preterm premature rupture of membranes treatment (ADAPT): a randomized controlled Phase I trial

BackgroundSeven days of antibiotics are recommended in the setting of preterm premature rupture of membranes (PPROM) to promote latency. Azithromycin has generally replaced a seven-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue which is why daily dosing is not always needed and local tissue, rather than plasma, concentrations are used to determine dosing. Based on limited pharmacokinetic studies in pregnancy, 1g one time dose of azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations (MIC50) for common genitourinary pathogens (50-500ng/ml). ObjectiveWe aim to compare the pharmacokinetics of one-time vs daily dosing of azithromycin in the setting of preterm pre-labor rupture of membranes (PPROM) Study DesignThis is a randomized clinical trial of singletons with PPROM randomized to 1gram oral azithromycin once or 500mg oral azithromycin daily x7 days. Primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at time points 1-4hrs and 12-24hrs after first dose, and then every 24hrs through 8 days. Amniotic fluid was collected opportunistically throughout the day noninvasively with Always Flex-foam pads. We aimed to enroll 20 participants to achieve N=5 still pregnant through 8 days in each group. Continuous variables compared with Mann Whitney U test and relationship between azithromycin concentration and time assessed with linear regression. ResultsThe study was halted after N=6 enrolled due to lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7weeks in the 1g group and 31.0±1.4 weeks in the 500mg daily group. One participant in each group had latency to delivery >7days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (p<0.001). Amniotic fluid concentration of azithromycin was relatively stable in the 1g once group (B=-0.07 (-0.44 – 0.31), p=0.71), in contrast, amniotic fluid concentration (ng/ml) increased over time (hours) in the 500mg daily group (B=1.3 (0.7 – 1.9), p<0.001). By ≥96hours median amniotic fluid levels of azithromycin were lower in the 1g once dosing group (median 11[7-56]) compared to 500mg daily (median 46 [23-196]), with a median difference -27 (-154 to -1), p=0.03. In plasma, there was higher azithromycin concentration during the first 24hrs with 1g once vs 500mg daily (median difference 637ng/ml (101-1547), p=0.01), however by ≥96hrs plasma azithromycin declined and was virtually undetectable in the 1g once group, while trough plasma levels in the 500mg remained elevated (median difference -207ng/ml (-271 to -155), p=0.03). Conclusion500mg daily dosing of azithromycin maintains higher amniotic fluid concentrations, and more consistently greater than common MICs, over eight days compared to 1g once in the setting of PPROM.

Is azithromycin associated with a reduction in acute placental inflammation in the setting of PPROM?

Following a national antibiotic shortage, azithromycin has been substituted for erythromycin in the setting of preterm premature rupture of membranes (PPROM) as adjuvant treatment to enhance gestational latency. While clinical outcomes are not inferior, azithromycin’s longer half-life and better tissue penetration has biological plausibility to be a superior antibiotic choice. Acute placental inflammation in the form of maternal (MIR) or fetal inflammatory response (FIR) has been described as a histological correlate and possible early signal for clinical chorioamnionitis.

Longitudinal evaluation of azithromycin and cytokine concentrations in amniotic fluid following one-time oral dosing in pregnancy.

To utilize noninvasive collection of amniotic fluid in the setting of preterm premature rupture of membranes (PPROMs) to report the time concentration profile of azithromycin in amniotic fluid over 7 days from a single dose, and evaluate the correlation between azithromycin concentration and inflammatory markers in amniotic fluid. Prospective cohort study of five pregnant patients admitted with PPROMs and treated with a single 1 g oral azithromycin dose. Amniotic fluid was collected from pads and used to quantify azithromycin concentration as well as TNFa, IL‐1a, IL‐1b, IL‐6, IL‐8, and IL‐10 concentrations. Primary outcome was time/concentration profile of azithromycin in amniotic fluid. Secondary outcome included correlation between azithromycin concentration and cytokine concentrations. Five patients were enrolled. Mean gestational age on admission with PPROM was 27.5 ± 2.3 weeks with a median latency of 7 days (interquartile range [IQR] = 4–13). A median of two samples/day (IQR = 1–3) were collected per participant. Azithromycin was quantified in duplicate; intra‐assay coefficient of variation was 17%. Azithromycin concentration was less than 60 ng/ml after day 3. Azithromycin concentration was positively correlated with IL‐8 (r = 0.38, p = 0.03), IL1a (r = 0.39, p = 0.03), and IL‐1b (r = 0.36, p = 0.04) in amniotic fluid. Azithromycin is detectable in amniotic fluid over 7 days from a single 1 g maternal dose, however, it is not sustained over the range of minimum inhibitory concentration for common genitourinary flora. Based on correlation with specific cytokines, azithromycin penetration in amniotic fluid may relate to maternal monocyte concentration in amniotic fluid in the setting of PPROM.

Preterm Premature Rupture of Membranes

Preterm premature rupture of membranes (PPROM) refers to rupture of the fetal membranes prior to 37-0/7 weeks’ gestation and prior to the onset of labor. PPROM complicates 2-4% of singleton pregnancies and 7-20% of twin pregnancies, and has been implicated in 30-40% of preterm births. Antepartum management involves confirming the diagnosis, excluding contraindications to expectant management (such as stillbirth, nonreassuring fetal testing, and intrauterine infection), and continued inpatient care with perinatology/NICU consultation, antenatal corticosteroids, broad-spectrum antibiotics (to prolong latency), and serial fetal surveillance. Delivery is indicated in the setting of nonreassuring fetal testing, intrauterine infection, excessive vaginal bleeding, preterm labor, and/or a gestational age of 34 weeks or beyond. Latency (time from rupture of membranes to delivery) depends on gestational age, severity of oligohydramnios, number of fetuses (shorter in twins), pregnancy complications (placental abruption, infection), fetal wellbeing, and use of broad-spectrum antibiotics. PPROM cannot be accurately predicted or prevented. Appropriate evidence-based management is essential to optimize outcome for both the mother and fetus in the setting of PPROM. This review contains 1 table, 2 figures and 57 references. Key words: chorioamnionitis, preterm birth, perinatal morbidity, twin pregnancies, preterm premature rupture of membranes (PPROM), fetal complications, maternal complications, labor and delivery, inpatient care, antepartum management

853 Length of stay and perinatal outcomes after preterm premature rupture of membranes between 28-33 weeks

Pregnancies complicated by preterm premature rupture of membranes (PPROM) are associated with adverse neonatal outcomes. Length of antepartum admission before delivery can serve as a proxy for duration of PPROM diagnosis. It is standard practice for women with PPROM to be managed on an inpatient antepartum unit. We sought to investigate the association between neonatal outcomes and length of antepartum admission in pregnancies complicated by PPROM. This is a retrospective cohort study of singleton, non-anomalous gestations complicated by PPROM in California between 2007-2011 using birth registry and ICD-9 data. We categorized antepartum admission stay as <7 days or ≥7 days. Gestational age at time of delivery ranged from 28-33 weeks gestation. We investigated the association between length of antepartum admission and adverse perinatal outcomes. Outcomes include newborn septicemia, chorioamnionitis, NICU admission >24 hours, neonatal death, respiratory distress syndrome (RDS), necrotizing enterocolitis, and intraventricular hemorrhage (IVH). Analyses utilized chi-square tests and multivariable logistic regression models. A p-value of less than 0.05 was considered statistically significant. In this cohort of 6,708 deliveries complicated by PPROM between 28-33 weeks gestational age, rates of chorioamnionitis were statistically lower in the cohort with <7 day length of stay compared to a length of stay ≥7 days (9.3% vs. 22.1%, p-value < 0.001) (Table 1). Rates of RDS were statistically lower in the cohort with <7 day length of stay compared to a length of stay ≥7 days (66.4% vs. 71.9%, p-value < 0.001). Rates of NICU admission were higher in the cohort with <7 day length of stay compared to a length of stay ≥7 days (92.5% and 90.3%, p-value = 0.009). Longer antepartum length of stay ≥7 days was associated with higher rates of chorioamnionitis and some adverse neonatal outcomes in the setting of PPROM during 28-33 weeks gestation.

The Effect of Non-penicillin Antibiotic Regimens on Neonatal Outcomes in Preterm Premature Rupture of Membranes.

Objective A 7-day course of a penicillin (PCN) and macrolide is standard of care (SAR) in preterm premature rupture of membranes (PPROM). Data regarding alternative antibiotic regimens are limited. We sought to assess the impact of non-PCN regimens on neonatal outcomes. Study Design Secondary analysis of randomized controlled trial of antenatal magnesium sulfate. Singleton, nonanomalous pregnancies complicated by PPROM at > 24 weeks of gestation receiving the SAR were compared with women receiving a non- β -lactam regimen and a macrolide (NPCR). Primary outcome was a neonatal composite. Secondary outcomes included pregnancy latency, endometritis, and chorioamnionitis. Results A total of 949 women met inclusion criteria; 821(56%) received the SAR and 128(8.8%) received NPCR. Adjusted models did not demonstrate worse outcomes (AOR [adjusted odds ratio] = 0.50; 95% CI [confidence interval]: 0.22–1.11). Neonates receiving SAR were less likely to have bronchopulmonary dysplasia (BPD; p = 0.03) but more likely to have severe necrotizing enterocolitis (sNEC; p = 0.04). Risk for chorioamnionitis and median latency did not differ between groups but women receiving the SAR were less likely to get endometritis (AOR = 0.35; 95% CI: 0.14–0.91). Conclusions In this cohort, receiving NPCR in the setting of PPROM did not impact the overall risk of adverse neonatal outcomes or latency, but did increase the risk of endometritis. Alterations in individual neonatal morbidities suggest follow-up studies are needed.

The effects of tocolysis on neonatal septic death in women with PPROM: a retrospective cohort study.

In women with preterm premature rupture of membranes (PPROM), particularly those with suspected chorioamnionitis, the benefit of tocolysis on neonatal outcome remains unclear. Our purpose was to evaluate the effect of tocolysis on neonatal septic death in women with PPROM with and without chorioamnionitis. A retrospective cohort study was used to address our study objective. We created a cohort consisting of all live births between 24 and 32weeks' gestation that were registered in the Linked Birth and Infant Death data files (2009-2013) from the United States. Multivariate logistic regression was used to evaluate the effect of tocolysis on neonatal septic death at 7 and 28days in births with and without chorioamnionitis. Of the 46,968 births that met our inclusion criteria, tocolysis was administered to 6264 (13.3%). Tocolysis was more commonly prescribed to Caucasians, smokers, in multiple birth pregnancies, and to women with a history of preterm births. Tocolysis was not significantly associated with neonatal septic death at 7days (OR 0.66, 95% CI 0.39-1.13) or at 28days (OR 0.85, 95% CI 0.60-1.19). This was consistent in pregnancies with and without chorioamnionitis. Furthermore, tocolysis was associated with a reduced risk of neonatal septic death at 7days when administered between 24 and 27weeks' gestation (OR 0.44, 95% CI 0.22-0.88). In the setting of PPROM, tocolysis does not appear to increase the risk of neonatal septic death at 7 and 28days. Therefore, consideration should be given to its administration if clinically indicated.

The Effects of Tocolysis on Neonatal Septic Death in Women With PPROM: A Retrospective Cohort Study [21Q

INTRODUCTION: The use of tocolysis in women with preterm premature rupture of membranes (PPROM) remains uncertain, particularly in suspected chorioamnionitis. The purpose of our study was to evaluate the effect of tocolysis on neonatal septic death in women with PPROM +/- chorioamnionitis. METHODS: Using the Linked Birth and Infant Death data files (2009-2013) from the National Center for Health Statistics, we conducted a retrospective cohort study on all registered live births between 24-32 weeks' of pregnancy in order to evaluate the effect of tocolysis on neonatal septic death at 7 and at 28 days among women with PPROM between 24 and 32 weeks' gestation. Logistic regression models were used to evaluate the effect of tocolysis on neonatal septic death at 7 and at 28 days in births with and without chorioamnionitis. RESULTS: There were 46,968 births that met study criteria, and of which 6,264 (13.3%) received tocolysis. Tocolysis was more commonly administered to women who were Caucasians, smokers, and with multiple birth pregnancies and previous preterm births. There was no significant association between tocolysis and neonatal septic death at 7 days (OR 0.66, 95% CI 0.39-1.13) and at 28 days (OR 0.85, 95% CI 0.60-1.19). This was consistent in pregnancies complicated by chorioamnionitis and those without chorioamnionitis. CONCLUSION: In the setting of PPROM, tocolysis does not appear to increase the risk of neonatal septic death. Therefore, consideration can be given to its administration if clinically indicated.

Rate of Spontaneous Version Following Preterm Premature Rupture of Membranes [28N

INTRODUCTION: Malpresentation is a common problem early in pregnancy. The rate of spontaneous version (SV) by gestational age has been studied, but is poorly understood after preterm premature rupture of membranes (PPROM), which complicates 3% of pregnancies in the United States. The objective of our study was to report the rate of SV following PPROM. METHODS: We conducted a retrospective cohort study on women age 18 or above with singleton intrauterine pregnancies who experienced PPROM between 22-34 weeks gestation and were delivered at the Mayo Clinic from 01/2010-12/2015. Demographic characteristics, obstetric history, and prenatal care details were abstracted through chart review. Aneuploidy, major fetal anomalies, maternal Müllerian anomalies, and delivery less than 24 hours after PPROM were excluded. RESULTS: Among 120 patients included in the study, 29 were nulliparous. Mean maternal age at PPROM diagnosis was 29.3 years. The median gestational age at PPROM diagnosis and at delivery was 31 1/7 weeks and 32 5/7 weeks, respectively. Intrauterine growth restriction was diagnosed in 10 women following PPROM. Sixty-nine (57.5%) patients delivered vaginally and 51 (42.5%) underwent cesarean section. Twenty-three (19.2%) women experienced SV following PPROM. Of the 21 breech presentations at PPROM diagnosis, 4 (19%) converted to cephalic presentation at delivery. CONCLUSION: We determined that approximately 1 out of 5 women experience SV in the setting of PPROM. Data about SV following PPROM is important in order to counsel patients about expectations for the remainder of their pregnancy. This new evidence can better prepare patients and providers for safe delivery.

Limiting the Exposure of Select Fetuses to Intrauterine Infection/Inflammation Improves Short-Term Neonatal Outcomes in Preterm Premature Rupture of Membranes

Background: To improve neonatal outcomes in pregnancies at heightened risk for early-onset neonatal sepsis (EONS), there is a need to identify fetuses that benefit from expectant management as opposed to early delivery. Detectable haptoglobin and haptoglobin-related protein (Hp&HpRP switch-on status) in cord blood has been proposed as a biomarker of antenatal exposure to intra-amniotic infection and/or inflammation (IAI), an important determinant of EONS. Subjects and Methods: We analyzed 185 singleton newborns delivered secondary to preterm premature rupture of membranes (PPROM). In 123 cases, amniocentesis was performed to exclude amniotic fluid (AF) infection. Delivery was indicated for 61 cases with confirmed infection. Women without AF infection (n = 62) and those without amniocentesis (n = 62) were managed expectantly. Interleukin 6 and Hp&HpRP switch-on status were evaluated by ELISA and Western blot. Newborns were followed prospectively for short-term outcomes until hospital discharge or death. Results: Newborns exposed antenatally to IAI had an increased risk of adverse neonatal outcome [OR: 3.0 (95% CI: 1.15-7.59)]. Increasing gestational age [OR: 0.61 (95% CI: 0.52-0.70)] and management with amniocentesis [OR: 0.37 (95% CI: 0.14-0.95)] lowered the newborn's risk of developing adverse outcomes. Discussion: In the setting of PPROM and IAI, early delivery benefits a select subgroup of fetuses that have not yet progressed to Hp&HpRP switch-on status.

Can a Composite Prognostic Index Predict Spontaneous Labor Onset in Preterm Premature Rupture of Membranes?

INTRODUCTION: Using retrospective evaluation of pregnancies complicated by preterm premature rupture of membranes (PPROM), this project developed a profile that can be used to predict onset of labor in the setting of PPROM. METHODS: Patients between 24 and 34 weeks of gestation admitted with PPROM during a 2-year period were evaluated retrospectively recording the following variables: vaginal cultures, cervical dilation, fetal heart rate, vaginal bleeding or discharge, and record of nursing concern. These variables were scored at four time points preceding the actual time of spontaneous labor onset. The model using the presence of dichotomous variables at 12 hours before the onset of labor was used to make the composite score. Each variable was assigned a number of points based on its β coefficient in the multivariate model. We set a cutoff score, determined by the receiver operating characteristic curves, that signified the likelihood of starting labor in 12 hours. RESULTS: There were statistically significant differences in all the variables at 12 hours before the labor. We arrived at a composite score that predicted the likelihood of labor within 12 hours while maintaining a significantly high negative predictive value. A score of 18 yielded a negative predictive value 80.5% and a positive predictive value of 52%. CONCLUSION: A composite prognostic index score was developed that helps anticipate onset of labor in patients with PPROM. This score may serve as a useful tool in settings where patients admitted with PPROM require transfer to labor units, magnesium sulfate for neuroprotection, or a rescue dose of steroids for optimal care.

Risk factors for unscheduled delivery in patients with placenta accreta

Patients with suspected placenta accreta have improved outcomes with scheduled delivery. Our objective was to identify risk factors for unscheduled delivery in patients with suspected placenta accreta. This was a cohort study of women with antenatally suspected placenta accreta. Women who delivered prior to a planned delivery date were compared with women who had a scheduled delivery. Data were analyzed using a Student t test, χ(2), logistic regression, and survival analyses. Variables included in the analyses were episodes of antenatal vaginal bleeding, preterm premature rupture of membranes (PPROM), uterine contractions, prior cesarean deliveries, interpregnancy interval, parity, and patient demographic factors. A value of P < .05 was considered significant. Seventy-seven women with antenatal suspicion for placenta accreta were identified. Thirty-eight (49.4%) had an unscheduled delivery. Demographics were similar between groups. Unscheduled patients delivered earlier (mean 32.3 vs 35.7 weeks, P < .001) and were significantly more likely to have had vaginal bleeding (86.8% vs 35.9%, P < .001) and uterine activity (47.4% vs 2.6%, P < .001). Each episode of antenatal vaginal bleeding was associated with an increased risk of unscheduled delivery (adjusted odds ratio, 3.8; 95% confidence interval, 1.8-7.8). Risk of earlier delivery was even greater when associated with PPROM (P < .001). Among women with suspected placenta accreta, those with antenatal vaginal bleeding were more likely to require unscheduled delivery. This risk increases further in the setting of PPROM and/or uterine contractions. These clinical factors should be considered when determining the optimal delivery gestational age for women with placental accreta.

690: Equivalence of erythromycin and azithromycin for treatment of PPROM

for treatment of PPROM Shari Gelber, Elyssa Brent, Aneesha Varrey, Bella Fridman, Katherine Sapra, William Frayer Weill Cornell Medical College, Obstetrics and Gynecology, New York, NY, Weill Cornell Medical College, Pediatrics, New York, NY, Columbia University, Pediatrics, New York, NY OBJECTIVE: A regimen of ampicillin and erythromycin (ERY) improves outcomes in patients with Preterm Premature Rupture of Membranes (PPROM). NationalshortagesofERY,patientsensitivitytoERY,andsimilar mechanism of action have encouraged providers to substitute Azithromycin (AZ). Some expert guidelines now recommend use of AZ, despite limited knowledge of efficacy in this setting. We sought to determine if treatment with AZ is equivalent to treatment with ERY for PPROM. STUDY DESIGN: Retrospective chart review of patients with PPROM admitted to labor and delivery at an academic center who received either ERY or AZ between January 2009 and March 2012. Inclusion criteria were gestational age 24-34 wk, planned expectant management and receipt of 1 dose of ERY or AZ. Exclusion criteria were delivery prior to receipt of antibiotics or receipt of both ERY and AZ. At our institution, decision to use AZ is determined by unavailability or patient intolerance of ERY and is not practitioner dependent. 2 and Fisher tests for categorical variables and Mann-Whitney test for continuous variables were done. Primary composite outcome was infant death, RDS, grade 3-4 IVH, NEC or sepsis 72 h of life. RESULTS: 103 patients met inclusion criteria; 7 were excluded for receiving both ERY/AZ. Data from 96 patients were analyzed. 67 patients received ERY and 29 patients received AZ. There were no statistically significant differences in age, ethnicity, BMI, GA at PPROM (ERY: 30.42 vs AZ: 30.85 p 0.53), history of preterm deliveries, parity, smoking, GBS status, or receipt of ampicillin or steroids between groups. There were no statistically significant differences in maternal or fetal outcomes between the groups(Table 1). There was no difference in latency (ERY: 65.6h vs AZ 61.7h). CONCLUSION: AZ provides the same benefit as ERY in the setting of PPROM. Although there is no significant difference in outcomes between groups, the trend toward improvement in several outcomes indicates studies are warranted to see if AZ is the preferred agent for PPROM.

Neonatal outcomes in the setting of preterm premature rupture of membranes complicated by chorioamnionitis

Objective. To examine the outcomes of neonates born to women with chorioamnionitis in the setting of preterm premature rupture of membranes (PPROM).Methods. A retrospective cohort study was conducted of deliveries with diagnosis of PPROM between 24 and 34 weeks of gestation at an academic medical center. Patients who delivered with the diagnosis of clinical chorioamnionitis were compared with patients who delivered without this diagnosis. Neonatal outcomes including Apgar scores, intracranial hemorrhage (ICH), sepsis, pneumonia, respiratory distress syndrome (RDS), and necrotizing enterocolitis (NEC) were assessed. Dichotomous outcomes were compared using chi-square test. Multivariable regression analyses were performed to control for potential confounding variables.Results. Of the 1153 patients diagnosed with PPROM, 29.0% were diagnosed with chorioamnionitis prior to delivery. Neonates born to mothers with a diagnosis of chorioamnionitis in the setting of PPROM had higher incidences (34.8%) of low 5-min Apgar scores, RDS, NEC, ICH, and pneumonia compared with 22.9% in neonates born to mothers without chorioamnionitis (p < 0.001).Conclusions. Patients who develop chorioamnionitis in the setting of PPROM are at higher risk for adverse neonatal outcomes compared with patients without chorioamnionitis in the setting of PPROM.

An evidence-based approach to the evaluation and treatment of premature rupture of membranes: Part II.

Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is responsible for one third of all preterm births. In part I of this series, the definition, pathophysiology, and diagnosis of PPROM was reviewed. In this part, treatment is discussed. Adjunctive antibiotic and corticosteroid therapy has the strongest evidence for improving neonatal outcome. Treatment is gestational age-dependent and will be influenced by local neonatal intensive-care unit (NICU) survival statistics. This review presents the available evidence and grades it according to the U.S. Preventative Task Force recommendations. After completion of this article, the reader should be able to summarize the data on the use of labor inhibition in the setting of PPROM, list potential antibiotics regimens that are recommended for prophylaxis in patients with PPROM, to describe the benefits of corticosteroid administration in patients with PPROM, and to outline potential management strategies for patients with PPROM based on gestational age.

Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers

Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers