Setting Of Preterm Premature Rupture 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.

Prophylactic anticoagulation for preterm premature rupture of membranes: a decision analysis

The current standard of care in the setting of preterm premature rupture of membranes involves antenatal hospitalization until delivery. The reduced physical activity during this time compounds the heightened risk for venous thromboembolism in pregnancy. Prophylactic anticoagulation can decrease this risk of venous thromboembolism; however, this benefit must be balanced against the risks of precluding neuraxial analgesia or increasing the risk of postpartum hemorrhage. The objective of this study was to determine the optimal modality for venous thromboembolism prophylaxis during hospitalization for preterm premature rupture of membranes using a decision analysis model. A decision-analytical Markov model was constructed using the TreeAge software comparing the use of unfractionated heparin, low-molecular-weight heparin or no anticoagulation in women with a singleton pregnancy who were hospitalized for preterm premature rupture of membranes after 24 weeks and remained hospitalized until delivery. Maternal outcomes examined included attainment of neuraxial analgesia (vs no analgesia for vaginal delivery or general anesthesia for cesarean delivery), venous thromboembolism, postpartum hemorrhage, and maternal death. Probabilities and utilities were derived from existing literature. Sensitivity analyses were performed to interrogate model assumptions, and a Monte Carlo probabilistic sensitivity analysis was performed to examine the robustness of the model. In this decision-analytical model, no prophylactic anticoagulation maximized maternal utilities. Clinical outcomes among a theoretical cohort of 100,000 women are shown in the Table. The 1- and 2-way sensitivity analyses supported this conclusion. Monte Carlo probabilistic sensitivity analysis indicated that no prophylaxis was the preferred choice in 56% of simulations, unfractionated heparin in 34% of simulations, and low-molecular-weight heparin in 10% of simulations. Our results do not support the routine use of prophylactic anticoagulation in women admitted to the hospital for preterm premature rupture of membranes. These findings can be used to inform clinical decisions when admitting low-risk singleton pregnancies to the hospital in the setting of preterm premature rupture of membranes.

Splenic rupture in an extremely low birthweight infant

Splenic rupture is a rare event in preterm and term infants. Symptoms of splenic rupture include acute blood loss, abdominal distention, and hypotension. We present the case of a 24 4/7 weeks gestation male infant born in the setting of preterm premature rupture of membranes who developed splenic rupture at 24 hours of life. Initially, the infant was managed medically. As the symptoms of abdominal compartment syndrome worsened, a bedside exploratory laparotomy was performed. The infant died on day of life 16 after developing hyperkalemia and pulmonary hemorrhage during an exchange transfusion for profound hyperbilirubinemia. This is the first report describing the management of splenic rupture in an extremely premature infant.

Antenatal Screening for Group B Streptococcus in the Setting of Preterm Premature Rupture of Membranes: Empiric versus Culture-based Prophylaxis.

Objective Imperfect culture sensitivity and increase of early onset neonatal sepsis (EONS) risk in preterm neonates raise concern that culture-based intrapartum antibiotic prophylaxis (IAP) may be insufficient after preterm premature rupture of membranes (PPROM). Our objective was to compare rates of EONS after empiric versus culture-based IAP in PPROM. Study Design This retrospective cohort study included women with a singleton gestation and PPROM between 23 and 33 weeks. Outcomes after culture-based IAP were compared with empiric IAP. The primary outcome was EONS. Secondary outcomes included group B streptococcus (GBS) bacteremia, bacteremia, and neonatal GBS infection. Bivariable and multivariable logistic analyses were performed. Results Of the 270 women who met inclusion criteria, 136 (50%) had culture-based IAP of whom 36 (26.5%) were GBS positive. There was no significant difference in bacteremia (2.2 vs. 4.5%, p = 0.30), GBS infection (0.8 vs. 0.7%, p = 1.00), or EONS (11.8 vs. 12.7%, p = 0.82) in infants of women with culture-based IAP compared with empiric IAP. Multivariable analysis confirmed a lack of advantage to empiric versus culture-based IAP in EONS risk (adjusted odds ratio [aOR] = 0.82, 95% confidence interval [CI]: 0.44–1.93). Conclusion In pregnancies complicated by PPROM, infants of women who received culture-based IAP had no significant difference in EONS or GBS infection compared with infants of women with empiric IAP.

Macrolide antibiotics roxithromycin vs. azithromycin for preterm premature rupture of membranes: a retrospective comparison.

Prophylactic antibiotics to prolong latency and reduce the risk of neonatal and maternal infections are used for preterm premature rupture of membranes. This study compared outcomes between two macrolides: roxithromycin given twice a day for a week and azithromycin, given as a single dose, which is more convenient. Two local protocols were retrospectively compared: roxithromycin and ampicillin from July 2005 to May 2016, and azithromycin and ampicillin from May 2016 to May 2018. Inclusion criteria were singleton pregnancy, at 24-34weeks of gestation upon admission with preterm premature rupture of membranes. Primary outcome was length of the latency period, defined as time from first antibiotic dose to 34 + 0weeks, or spontaneous or indicated delivery prior to 34 + 0weeks. Secondary outcomes were rates of chorioamnionitis, delivery mode, birth weight and Apgar scores. A total of 207 women met inclusion criteria, of whom, 173 received penicillin and roxithromycin and 34 received penicillin and azithromycin. Baseline characteristics were similar between groups. The latent period was longer in the azithromycin group than in the roxithromycin group (14.09 ± 14.2days and 7.87 ± 10.2days, respectively, P = 0.003). Rates of chorioamnionitis, cesarean deliveries, Apgar scores and birth weights were similar between the groups. Azithromycin compared to roxithromycin results in a longer latency period in the setting of preterm premature rupture of membranes at 24-34weeks of gestation. Given its more convenient regimen and our results, it seems justified to use azithromycin as the first-line treatment for patients with preterm premature rupture of membranes.

Treatment with inhaled nitric oxide is associated with improved survival in preterm neonates diagnosed with pulmonary hypoplasia

Purpose: We conducted this study to test our hypothesis that inhaled nitric oxide (iNO) therapy is associated with improved survival in preterm neonates with pulmonary hypoplasia (PH). In the setting of preterm premature rupture of membranes (PPROM), an otherwise normally developed fetus may develop PH. PPROM-associated PH often presents as severe hypoxic respiratory failure and may be complicated by persistent pulmonary hypertension (PPHN). Given the high mortality rate of PH among preterm neonates, many neonatologists prescribe iNO as a rescue therapy despite the limited evidence of its safety and effectiveness in this patient …

693: Tocolysis the setting of preterm premature rupture of membranes

Tocolysis after PPROM is controversial, and evidence to guide management is limited. We sought to determine if tocolysis after PPROM is associated with adverse neonatal outcomes. This is a secondary analysis of a randomized trial of magnesium for neuroprotection. Women at 24-32 weeks with singleton gestations and PPROM were eligible. We excluded women tocolyzed prior to randomization, fetuses with chromosomal or single gene abnormalities, and those with incomplete outcome data. The primary exposure was post randomization tocolysis. The primary neonatal outcome was culture proven sepsis, and the primary childhood outcome was a composite of death or Bayley scores 2 standard deviations below the mean at age 2 (score <70). Death is included as a competing outcome. Patient characteristics were compared by exposure. We fit logistic regression models to adjust for factors that influence odds of the outcomes including exposure to magnesium, race, education level, gestational age at birth, maternal BMI and smoking status. Of 1667 patients, 38 (2.3%) received tocolysis while 1629 (97.7%) did not. The most common tocolytic agent was magnesium (42.1%). Maternal age, race and BMI were similar among groups. Women in the tocolysis group were more educated, more likely to have multiple courses of steroids, and less likely to smoke. Neonates of tocolyzed women were larger (1687g v 1439g, p=0.01) and delivered at a later gestational age (31+1 v 29+6 weeks, p=0.01). Rates of neonatal sepsis were similar in tocolyzed versus non-tocolyzed groups (6 (15%) v 260 (16%), p=0.9). In the adjusted model the odds for sepsis and abnormal psychomotor developmental index (PDI) or death were elevated with tocolysis, although this finding did not reach statistical significance. There was no difference in abnormal mental developmental index (MDI) or death. Although the neonates of mothers given tocolysis prolonged gestation and achieved higher birth weights, tocolysis after PPROM may be harmful given possible increase risks for sepsis and low Bayley PDI/death. Further data are needed to verify findings and guide practice.

Frequency and clinical significance of short cervix in patients with preterm premature rupture of membranes.

ObjectiveCervical length measurement has been uggested as a useful tool for predicting intra-amniotic infection/inflammation in preterm labor, but little information is available in the setting of preterm premature rupture of membranes (pPROM). We aimed to determine whether a short cervical length is independently associated with an increased risk of intra-amniotic infection or inflammation and impending preterm delivery in women with pPROM.MethodsThis was a retrospective cohort study involving 171 consecutive singleton pregnant women with pPROM (21+0–33+6 weeks’ gestation), who underwent amniocentesis. Amniotic fluid (AF) was cultured, and assayed for interleukin (IL)-6 and IL-8. Cervical length was measured at the time of amniocentesis by transvaginal ultrasonography with an aseptic technique. Short cervical length was defined as a cervical length of ≤15 mm. Intra-amniotic infection was defined as a positive AF culture for microorganisms and intra-amniotic inflammation was defined as elevated AF concentrations of IL-6 or IL-8 (IL-6 ≥1.5 ng/mL and/or IL-8 ≥1.3 ng/mL).ResultsFifty (29.2%) women had a sonographic cervical length of ≤15mm. On univariate analysis, short cervical length was associated with an increased risk for intra-amniotic infection and/or inflammation; no other parameters studied showed a significant association. Multivariable analyses indicated that short cervical length was significantly associated with a higher risk of impending preterm delivery (within 2 days of measurement, within 7 days of measurement, and before 34 weeks), and remained significant after adjustment for potential confounders.ConclusionIn women with pPROM, short cervical length is associated with an increased risk for intra-amniotic infection/inflammation and associated with impending preterm delivery, independent of the presence of intra-amniotic infection/inflammation.

Perinatal Outcomes in Cephalic Compared With Noncephalic Singleton Presentation in the Setting of Preterm Premature Rupture of Membranes Before 32 Weeks of Gestation.

To investigate the relationship between fetal presentation at the time of admission for preterm premature rupture of membranes (PROM) and perinatal outcomes, including gestational latency, among women in a large and well-characterized population with preterm PROM at less than 32 weeks of gestation. This was a secondary analysis of data from women randomized to receive magnesium sulfate compared with placebo in the previously reported Maternal-Fetal Medicine Units Network Beneficial Effects of Antenatal Magnesium Sulfate (1997-2004) trial. Women with a singleton gestation and preterm PROM were included. Fetal presentation at the time of randomization was recorded. Associations of fetal position (cephalic compared with noncephalic) with perinatal outcomes were compared using χ, Fisher exact, and Wilcoxon rank-sum tests. Perinatal outcomes included gestational latency, abruption, and neonatal morbidity and mortality. Multivariable regression (logistic, linear, and Cox) analyses were used to adjust for potential confounding factors. Of the 1,767 eligible women, 439 (24.5%) had a noncephalic presentation. Noncephalic presentation was associated with an earlier median gestational age at the time of preterm PROM (26.6 compared with 28.4 weeks of gestation, P<.001), but no difference in gestational latency (7.5 compared with 7.7 days, P=.7, adjusted hazard ratio 1.09, 95% confidence interval [CI] 0.97-1.23). There were no differences in odds of abruption or neonatal morbidity in multivariable analyses. However, even after controlling for potential confounding factors including gestational age at delivery and mode of delivery, odds of neonatal death before discharge was greater for noncephalic gestations (11.5% compared with 3.4%, P<.001; adjusted odds ratio 2.24, 95% CI 1.12-4.48). Even after controlling for gestational age and route of delivery, noncephalic fetuses in the setting of preterm PROM are at greater risk of neonatal death.

670: Perinatal outcomes in cephalic versus noncephalic singleton presentation in the setting of preterm premature rupture of membranes

670: Perinatal outcomes in cephalic versus noncephalic singleton presentation in the setting of preterm premature rupture of membranes

3: Aspirin for preeclampsia prevention, latency and chorioamnionitis in preterm premature rupture of membranes

Low dose aspirin (ASA) is recommended to prevent preeclampsia (PEC) in at-risk patients. Low dose ASA is known to cause decreased leukocyte adhesion and prostaglandin inhibition. The effects of decreased leukocyte adhesion and prostaglandin inhibition on rates of chorioamnionitis (chorio) is unknown. We hypothesize that ASA-induced decreased leukocyte adhesion will increase the rate of chorioamnionitis (chorio). We hypothesize that in the setting of preterm premature rupture of membranes (PPROM) prostaglandin inhibition prolongs latency and increases rates of chorio.

759: Unexpected finding in vaginal microbiome assessment in PPROM

Altered vaginal microbial population and subclinical infection have long been posited as major contributors to preterm birth, the leading cause worldwide for infant morbidity and mortality. We sought to describe the vaginal microbiome using high throughput genomic technology in the setting of preterm premature rupture of membranes (PPROM).

Outcomes in cephalic vs noncephalic presentation in the setting of preterm premature rupture of membranes

This study was conducted to determine whether fetal position at the time of preterm premature rupture of membranes (PPROM) diagnosis affects outcomes. A retrospective study was designed to assess differences in outcomes between cephalic and noncephalic presentation at PPROM diagnosis between 24 and 34 weeks' gestation. Five hundred sixty-six cases of PPROM were identified; 108 cases (19.1%) were noncephalic at time of PPROM diagnosis. The 2 groups were similar with regard to demographics. Although membrane rupture and delivery occurred earlier in the noncephalic group, there was no difference in latency between groups (cephalic group, 6.22 days vs noncephalic group, 7.85 days; P = .07). Noncephalic pregnancies were substantially more likely to be complicated by oligohydramnios, abruption, intrauterine fetal death, and infectious morbidity. Noncephalic presentation at the time of diagnosis of PPROM independently and significantly increases the risk of maternal complications in such affected pregnancies.

493: Cerclage retention versus removal in the setting of preterm premature rupture of membranes: a systematic review and meta-analysis of neonatal sepsis and mortality

When PPROM occurs in patients with a cerclage, there is no consensus regarding its removal or retention. The objective of this study was to perform a meta-analysis of the neonatal effects associated with cerclage retention versus removal in the setting of PPROM.

Preterm premature rupture of membranes, chorioamnion inflammatory scores and neonatal respiratory outcome

To evaluate whether histological chorioamnionitis (HCA), in the setting of preterm premature rupture of membranes (PPROM), affects infant respiratory outcome. A prospective histological study on 287 consecutive placentas was performed in preterm infants (<or=32(+6) weeks gestation), categorised into four groups: according to the presence or absence of HCA, in the setting or in absence of PPROM. Neonatal intensive care unit, Department of Pediatrics, Padua University, Padua, Italy from January 2001 to December 2006. Among the 287 NICU admitted preterm infants, 68/287 (23.6%) presented with HCA, 16/68 (23.5%) with a coexisting fetal inflammatory response, and 74/287 (25.7%) with PPROM. HCA was associated with a greater frequency of vaginal delivery (P < 0.0001), lower gestational age (P < 0.0001) and lower birth weight (P < 0.01). HCA had no effect on fetal lung maturation, however, it was a significant risk factor for CLD (RR; 95% CI 2.08; 1.30-3.33). HCA and the fetal inflammatory response were also significant risk factors for PPROM (RR; 95% CI 2.07; 1.42-3.03 and 2.64; 1.71-4.09 respectively). Conversely, HCA in the setting of PPROM failed to reveal any RDS protection or subtype CLD risk. Multivariate analysis demonstrated significant independent effects of presence of maternal HCA (P = 0.04), gestational age (P < 0.0001) and interaction HCA-gestational age (P = 0.04) on CLD development, regardless of the presence of fetal HCA or fetal HCA-gestational age interaction, PPROM or PPROM-gestational age interaction. Histological chorioamnionitis is a significant PPROM and CLD risk factor, but it fails to provide any protection from RDS. HCA in the setting of PPROM also failed to reveal any RDS protection or subtype CLD risk.

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.

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

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

Multiple assessment techniques evaluate antepartum fetal risks.

As technology has advanced, the field of antepartum fetal evaluation has grown. As reviewed here, a variety of options are available for use in the complicated pregnancy, including application of fetal heart rate monitoring techniques, noninvasive assessment of amniotic fluid volume, sonographic evaluation of fetal behavior, and Doppler assessment of fetal blood flow. It remains unclear which test is the best for any particular situation. The NST is the simplest test to perform but has a higher false-positive rate than the biophysical profile or the CST. These two tests also appear to demonstrate superior sensitivity, at the expense of increased testing time and cost. The application of vibroacoustic stimulation improves the specificity of the NST, while the addition of a sonographic assessment of amniotic fluid volume increases sensitivity and creates an acceptable alternative as a primary test. The limited biophysical profile, with the NST component initially omitted, provides some savings in time and cost without apparent loss of sensitivity or specificity when compared with the full profile. Ultimately, while one particular technique of fetal assessment may never prove to be the best, certain techniques may have advantages over others in particular clinical situations. Umbilical artery Doppler velocimetry appears to be a useful adjunct to other forms of testing, especially in the pregnancy at risk for intrauterine growth restriction and pre-eclampsia. Recent data have shown the biophysical profile predicts the onset of amnionitis in the setting of preterm premature rupture of membranes (PROM). The sonographic assessment of amniotic fluid volume is particularly important in the serial evaluation of the pregnancy complicated by fetal growth restriction. As new technology leads to innovative forms of testing, it is expected that these new tests of fetal status will similarly add to, rather than replace, the existing items in our armamentarium.