Kent Heyborne

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes

OBJECTIVE The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes. STUDY DESIGN Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). RESULTS The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively). CONCLUSION We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

Amniocentesis in the management of preterm premature rupture of the membranes: A retrospective cohort analysis

Objective. This retrospective analysis determined the utility of amniocentesis in the management of preterm premature rupture of the membranes (PPROM). Study design. Consecutive patients with PPROM were managed with and without amniocentesis. Both groups received antibiotics and corticosteroids; tocolytics were withheld. Patients were induced if clinical or amniotic fluid (AF) proven chorioamnionitis occurred or gestational age goals were reached. Primary endpoints were individual and composite neonatal morbidity (CNM). Results. One hundred forty-seven maternal patients were managed with amniocentesis (AC) and 146 were managed without amniocentesis (NAC). CNM was significantly reduced in the group managed with AC (OR 2.94, 95% CI 1.68–5.15, NAC vs. AC). NAC patients had similar rates of neonatal sepsis as well as CNM to those patients in the AC group with positive AF Gram stains and/or cultures. Conclusions. Patients with PPROM who are managed with AC have significantly less CNM than NAC patients.

17-hydroxyprogesterone caproate for preterm rupture of the membranes: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Selective delivery in a twin gestation

One or more infants of a multifetal pregnancy occasionally require delivery selectively because of in utero risk of fetal death in circumstances in which the sibling fetus appears well. At 26 weeks 5 days of gestation a small fundally placed twin in a dichorionic gestation had an estimated fetal weight of 650 g with decreased amniotic fluid and ominous Doppler velocity findings in his umbilical artery. A normally grown presenting sibling had reassuring fetal surveillance data. Over a 2-week interval the growth-restricted twin showed no growth, and his status deteriorated. He was selectively delivered by hysterotomy. Selective delivery may offer parents of multifetal gestations an additional option when 1 or more of their fetuses are at high risk for in utero death.

Body Mass Index and the Spontaneous Onset of Parturition.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and the onset of parturition throughout gestation. METHODS: This was a secondary analysis of the Maternal-Fetal Medicine Units Network Preterm Prediction Study. Time-to-spontaneous-birth-event (ie, “survival”) methods were used to study the association of BMI with the timing of spontaneous onset of labor throughout gestation with indicated births censored at delivery. A Kaplan-Meier estimate of the probability of spontaneous labor was compared with a log rank test across five categories of BMI (kg/m2): underweight (less than 18.5), normal weight (18.5–24.99), preobese (25–29.99), obese I (30–34.99), and obese II+ (35 or greater). A proportional hazards model was estimated to compare time to spontaneous onset of labor adjusted for multiple variables known to be associated with the onset of labor. RESULTS: Normal-weight women (n=1,054) had a median delivery gestational age of 39 3/7 weeks. Obese II+ women (n=178) had a median delivery gestational age 5 days later than normal-weight women (P<.001). Delivery gestational age of preobese (n=866) and obese I (n=548) women was not significantly different from normal-weight women. Underweight women (n=41) had a median delivery gestational age 5 days earlier than normal-weight women (P<.001). Compared with women with normal BMIs, obese II+ women were significantly less likely and underweight women significantly more likely to enter spontaneous labor at all gestational ages. In the multivariable model, BMI was significantly associated with spontaneous onset of labor throughout pregnancy (BMI [five-unit] adjusted hazard ratio 0.874, 0.829–0.921). CONCLUSION: Body mass index is significantly associated with the likelihood of the spontaneous onset of labor at all gestational ages with gestational age at the time of delivery and BMI being inversely related. This novel observation unifies previous reports focusing on the association of overweight and underweight BMIs and preterm and postterm birth and may inform discussions surrounding elective induction of labor at term.

Baseline placental growth factor levels for the prediction of benefit from early aspirin prophylaxis for preeclampsia prevention

OBJECTIVE Placental growth factor (PlGF) levels early in pregnancy are lower in women who ultimately develop preeclampsia. Early initiation of low-dose aspirin reduces preeclampsia risk in some high risk women. We hypothesized that low PlGF levels may identify women at increased risk for preeclampsia who would benefit from aspirin. STUDY DESIGN Secondary analysis of the MFMU High-Risk Aspirin study including singleton pregnancies randomized to aspirin 60mg/d (n=102) or placebo (n=72), with PlGF collected at 13w 0d-16w 6d. Within the placebo group, we estimated the probability of preeclampsia by PlGF level using logistic regression analysis, then determined a potential PlGF threshold for preeclampsia prediction using ROC analysis. We performed logistic regression modeling for potential confounders. RESULTS ROC analysis indicated 87.71pg/ml as the threshold between high and low PlGF for preeclampsia-prediction. Within the placebo group high PlGF weakly predicted preeclampsia (AUC 0.653, sensitivity/specificity 63%/66%). We noted a 2.6-fold reduction in preeclampsia with aspirin in the high-PlGF group (12.15% aspirin vs 32.14% placebo, p=0.057), but no significant differences in preeclampsia in the low PlGF group (21.74% vs 15.91%, p=0.445). CONCLUSIONS Unlike other studies, we found that high rather than low PlGF levels were associated with an increased preeclampsia risk. Low PlGF neither identified women at increased risk of preeclampsia nor women who benefitted from aspirin. Further research is needed to determine whether aspirin is beneficial in women with high PlGF, and whether the paradigm linking low PlGF and preeclampsia needs to be reevaluated. CONDENSATION High-risk women with low baseline PlGF, a risk factor for preeclampsia, did not benefit from early initiation of low-dose aspirin.

17-hydroxyprogesterone caproate for preterm rupture of the membranes

OBJECTIVE Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Do maternal obesity or smoking explain the lack of effectiveness of 17-alpha hydroxyprogesterone caproate?

1 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 TO THE EDITORS: We thank Nelson et al for their recent study showing lack of efficacy of 17-alpha hydroxyprogesterone caproate (17OHP-C) for the prevention of recurrent preterm birth in their population. The adoption of 17OHP-C into widespread clinical practice based primarily on a single trial is somewhat unusual, and further validation is certainly warranted. Like these authors, we anxiously await the results of the PROLONG trial. Nelson et al raise valid concerns regarding the generalizability of randomized controlled trials. The salient issue thus becomes “What specific patient (or other) factors limit generalizability?” We have previously published on the importance of maternal weight and bodymass index (BMI) aswell asmaternal smoking status in mediating the effectiveness of 17OHP-C. We suggest that either or both of these patient characteristics may be important in explaining results of Nelson et al. In a secondary analysis of the original Meis et al cohort, we reported that 17OHP-C was primarily effective in smokers and less effective in nonsmokers. Nelson et al do not report smoking status, an important risk factor for preterm birth, for their prospective cohort. However, as cigarette use in general has decreased over time, their cohort may have included fewer smokers than the 22% in the trial of Meis et al. In another secondary analysis, we reported that fixeddose (250 mg) 17OHP-C is ineffective in women with a BMI 30, which includes 43% of the patients studied by Nelson et al as compared with 29% in the trial of Meis et al. We speculated in our report that the lack of effect of fixeddose 17OHP-C in obese women may be at least partially related to inadequate serum levels. Caritis et al reported that a threshold level of 17OHP-C may be necessary to achieve efficacy. While Nelson et al did not find a significant difference in median 17OHP-C levels between women with deliveries <35 and >35 weeks, this may not be the ideal comparison when reaching a critical threshold is needed. It appears from their Figure 2 that a substantial proportion of patients had 24-week levels in the lowest quartile reported by Caritis et al, a level associated with a high risk of recurrent preterm birth.

17-hydroxyprogesterone caproate for preterm rupture of the membranes: A multicenter, randomized, double-blind, placebo-controlled trial Presented in poster format at the 35th annual meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, Feb. 2-7, 2015.

OBJECTIVE Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.