Mechanism of Human Fetal Membrane Biomechanical Weakening, Rupture and Potential Targets for Therapeutic Intervention.

Using a novel in vitro model system combining biochemical/histologic with bioengineering approaches has provided significant insights into the physiology of fetal membrane weakening and rupture along with potential mechanistic reasons for lack of efficacy of currently clinically used agents to prevent preterm premature rupture of the membranes (pPROM) and preterm births. Likewise, the model has also facilitated screening of agents with potential for preventing pPROM and preterm birth.

Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells.

AIM: To investigate the role of thrombospondin motifs 9 (ADAMTS9) in preterm premature rupture of membranes (pPROM). MATERIALS AND METHODS: ADAMTS9 levels were measured in amnion cells from 24 patients of different groups (preterm vs. full-term birth, with vs. without PROM). ADAMTS9 was suppressed in human amnioblasts to investigate its effects on embryonic membrane cells and inflammation-induced cell damage. Pregnant mouse models were used to assess whether inflammation regulates ADAMTS9 by upregulating TNF-α and IL-6, contributing to the preterm birth occurrence. KEY FINDINGS: We found that ADAMTS9 protein and gene expression levels significantly differed among various groups (pPROM > full-term PROM > preterm non-PROM > full-term non-PROM). After ADAMTS9 suppression in human amnioblast WISH cells, TNF-α- and IL-6-induced apoptosis was decreased. In addition, TNF-α, IL-6, and ADAMTS9 protein and gene expression levels were increased in the embryos of mice treated with LPS compared with controls. In agreement, the rate of preterm birth was higher in the LPS group compared with controls. SIGNIFICANCE: Taken together, these in vitro and in vivo findings suggest that TNF-α and IL-6 secreted by macrophages during inflammation regulate ADAMTS9 and induce pPROM.

Interleukin-6 measured using the automated electrochemiluminescence immunoassay method for the identification of intra-amniotic inflammation in preterm prelabor rupture of membranes.

Introduction: We aimed to compare the amniotic fluid interleukin (IL)-6 concentrations measured using the automated electrochemiluminescence immunoassay method and ELISA, and to establish an IL-6 concentration cut-off value for intra-amniotic inflammation (IAI) in preterm prelabor rupture of membranes (PPROM), which can be used in the automated electrochemiluminescence immunoassay method.Materials and methods: A total of 120 women with PPROM were included in this study. Amniotic fluid samples were obtained through transabdominal amniocentesis. IL-6 concentrations were assessed using both the automated electrochemiluminescence immunoassay method and ELISA, the current gold standard. IAI was defined as an amniotic fluid IL-6 concentration of ≥2600 pg/mL measured using ELISA.Results: A correlation between both assays was found (Spearman's rho = 0.97; p < .0001). Based on the receiver-operating characteristic curve for the identification of IAI (area under the curve = 0.99), a cut-off value of ≥3000 pg/mL was selected for the automated electrochemiluminescence immunoassay method with a sensitivity of 88%, specificity of 99%, positive predictive value of 97%, negative predictive value of 96%, and likelihood ratio of 76.Conclusions: For amniotic fluid IL-6 concentrations assessed using the automated electrochemiluminescence immunoassay method, a cut-off value of 3000 pg/mL was indicated for diagnosing IAI in women with PPROM.

Influence of perinatal inflammation on the neurodevelopmental outcome of premature infants.

OBJECTIVE: To evaluate the influence of perinatal inflammation on neurodevelopmental outcome of premature infants. STUDY DESIGN: From a retrospective cohort study of women with preterm labor with intact membranes or preterm prelabor rupture of membranes (PPROM) with an amniocentesis to rule out intra-amniotic inflammation (IAI) and microbial invasion of the amniotic cavity (MIAC), we evaluated neurodevelopmental outcome of their infants born between 24.0 and 34.0 weeks gestation. Women with clinical chorioamnionitis at admission were excluded. Neurodevelopmental outcome was screened with the Ages & Stages Questionnaire (ASQ)-3. We analyzed the relationship between an altered ASQ-3 and antenatal, intra-partum and post-partum factors related to perinatal inflammation. RESULT: Among 98 infants evaluated, 22% had an abnormal score. Amniotic fluid interleukin-6 levels and early-onset sepsis (EOS) were independent factors of an altered ASQ-3 with delivery <26.0 weeks being the strongest predictor. CONCLUSIONS: In premature infants, the presence of IAI, delivery <26.0 weeks and EOS were found to be independent factors of an altered ASQ-3.

[In the case of premature live birth, is very early rupture of the membranes an additional risk factor for morbidity and mortality?] / En cas de naissance vivante prématurée, la rupture très précoce des membranes est-elle un facteur de risque supplémentaire de morbi-mortalité ?

OBJECTIVE: To describe survival rate after preterm premature rupture of membranes (PPROM) before 25 weeks of gestation and compare neonatal morbidity and mortality among those born alive with a control group of infants born at a similar gestational age without premature rupture of membranes. METHODS: We conducted a retrospective single-centre study at Port-Royal maternity, from 2007 to 2015, comparing neonatal outcomes between liveborninfants exposed to PPROM prior to 25 weeks of gestation (WG) and a control group not exposed to premature rupture of the membranes. For each live-born child, the next child born after spontaneous labor without PPROM was matched for gestational age at birth, sex, and whether or not they received antenatal corticosteroid therapy. The primary endpoint was severe neonatal complications assessed by a composite endpoint including neonatal deaths, grade 3-4 HIV, bronchopulmonary dysplasia, leukomalacia and stade 3-4 retinopathies. RESULTS: Among 77 cases of very premature rupture of the membranes, 55 children were born alive. Among these, the average gestational age at birth was 28 WG and 1 day. The rate of severe neonatal complications did not differ between the two groups (43.6% in the PPROM group vs. 36.4%, P=0.44) and the survival rate at discharge was also similar in the two groups (85.5% vs. 83.6%, P=0.98). CONCLUSIONS: In our cohort and among livebirths after 24 WG, PPROM before 25 WG was not associated with an increased risk of morbidity and mortality compared to children born at the same gestational age after a spontaneous labor with intact membranes.

Fetal Urine Production Rate in Preterm Premature Rupture of Membranes Is Associated with Adverse Neonatal Outcome: A Pilot Study.

AIM: In this study, we evaluate the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM). METHODS: We conducted a prospective pilot cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later managed until spontaneous labor (after 48 h of admission), chorioamnionitis, or induction by protocol at 35 + 0 weeks. FUPR was evaluated by 2D sonography at admission (corrected for gestational age). The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate (<4 mL/kg/h), and early neonatal sepsis. Samples of maternal (at admission) and umbilical cord blood were analyzed for interleukin-6 (IL-6) level. RESULTS: The study included 38 women. Low FUPR was associated with clinical chorioamnionitis, longer NICU hospitalization (p = 0.01), higher rates of NEC or IVH (p = 0.008), and blood transfusion (p = 0.004). CONCLUSIONS: A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of adverse neonatal outcome.

Pulmonary hypoplasia.

To survive the transition to extrauterine life, newborn infants must have lungs that provide an adequate surface area and volume to allow for gas exchange. The dynamic activities of fetal breathing movements and accumulation of lung luminal fluid are key to fetal lung development throughout the various phases of lung development and growth, first by branching morphogenesis, and later by septation. Because effective gas exchange is essential to survival, pulmonary hypoplasia is among the leading findings on autopsies of children dying in the newborn period. Management of infants born prematurely who had disrupted lung development, especially at the pre-glandular or canalicular periods, may be challenging, but limited success has been reported. Growing understanding of stem cell biology and mechanical development of the lung, and how to apply them clinically, may lead to new approaches that will lead to better outcomes for these patients.

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

OBJECTIVE: Cervical 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. METHODS: This 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). RESULTS: Fifty (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. CONCLUSION: In 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.

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes.

BACKGROUND: Premature prelabor rupture of fetal membranes accounts for 30% of all premature births and is associated with detrimental long-term infant outcomes. Premature cervical remodeling, facilitated by matrix metalloproteinases, may trigger rupture at the zone of the fetal membranes overlying the cervix. The similarities and differences underlying cervical remodeling in premature prelabor rupture of fetal membranes and spontaneous preterm labor with intact membranes are unexplored. OBJECTIVES: We aimed to perform the first transcriptomic assessment of the preterm human cervix to identify differences between premature prelabor rupture of fetal membranes and preterm labor with intact membranes and to compare the enzymatic activities of matrix metalloproteinases-2 and -9 between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. STUDY DESIGN: Cervical biopsies were collected following preterm labor with intact membranes (n = 6) and premature prelabor rupture of fetal membranes (n = 5). Biopsies were also collected from reference groups at term labor (n = 12) or term not labor (n = 5). The Illumina HT-12 version 4.0 BeadChips microarray was utilized, and a novel network graph approach determined the specificity of changes between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. Quantitative reverse transcription-polymerase chain reaction and Western blotting confirmed the microarray findings. Immunofluorescence was used for localization studies and gelatin zymography to assess matrix metalloproteinase activity. RESULTS: PML-RARA-regulated adapter molecule 1, FYVE-RhoGEF and PH domain-containing protein 3 and carcinoembryonic antigen-ralated cell adhesion molecule 3 were significantly higher, whereas N-myc downstream regulated gene 2 was lower in the premature prelabor rupture of fetal membranes cervix when compared with the cervix in preterm labor with intact membranes, term labor, and term not labor. PRAM1 and CEACAM3 were localized to immune cells at the cervical stroma and NDRG2 and FGD3 were localized to cervical myofibroblasts. The activity of matrix metalloproteinase-9 was higher (1.22 ± 4.403-fold, P < .05) in the cervix in premature prelabor rupture of fetal membranes compared with preterm labor with intact membranes. CONCLUSION: We identified 4 novel proteins with a potential role in the regulation of cervical remodeling leading to premature prelabor rupture of fetal membranes. Our findings contribute to the studies dissecting the mechanisms underlying premature prelabor rupture of fetal membranes and inspire further investigations toward the development of premature prelabor rupture of fetal membranes therapeutics.

Clínicas Perinatológicas Argentinas 2017 / Argentine Perinatologics Clinics 2017

En este número se reúne material sobre actualidad de la medicina perinatal, psicología perinatal, trato obstétrico inadecuado, y etiología de la rotura prematura de membranas durante el embarazo.

Outcome at Two Years of Very Preterm Infants Born after Rupture of Membranes before Viability.

PURPOSE: To compare the respiratory and neurological outcomes at two years of age of preterm children born before 33 weeks of gestation (WG) after early preterm premature rupture of membranes (EPPROM) between 14 and 24 WG with preterm children without EPPROM. DESIGN AND PATIENTS: This single-center case-control retrospective study was conducted at Rouen University Hospital between 1st January 2000 and 31st December 2010. All the cases with EPPROM born from 26WG to 32WG were included. Each newborn was matched by sex, gestational age (GA) and year of birth to two very preterm children, born without EPPROM. At two years of corrected age, motor and cognitive abilities were assessed by routine score based on the Amiel-Tison and Denver developmental scales. RESULTS: Ninety-four cases with EPPROM before 24WG have been included. The 31 children born from 26WG to 32WG were matched with 62 controls. The EPPROM group had poorer clinical evaluation at one year for motor (p = 0.003) and cognitive developmental scores (p = 0.016). Neuromotor rehabilitation was performed more often (p = 0.013). However, there was no difference at 2 years of age. Children born after EPPROM were hospitalized more often for bronchiolitis (p<0.001) during their first 2 years, which correlates with increased incidence of pneumothorax (p = 0.017), pulmonary hypoplasia (p = 0.004) and bronchopulmonary dysplasia (p = 0.005) during neonatal period. CONCLUSION: At two years, despite an increase in severe bronchiolitis and the need for more neuromotor rehabilitation during the first month of the life after discharge, there was no difference in neurological outcomes in the very preterm children of the EPPROM group compared to those born at a similar GA without EPPROM.

Evaluation of perinatal outcomes in pregnant women with preterm premature rupture of membranes / Avaliação dos resultados perinatais em gestantes com rotura prematura das membranas pré-termo

SUMMARY Objective: To determine the association between amniotic fluid index (AFI) and perinatal outcomes in preterm premature rupture of membranes (PPROM). Method: A retrospective cohort study was conducted between 2008 and 2012. 86 pregnant women were included, with a diagnosis of PPROM and gestational age from 24 to 35 weeks. Women who presented hypertensive disorders, diabetes, fetuses with birth defects and infection at admission were excluded. To determine the association between AFI and perinatal outcomes, chi-square and Fisher’s exact test were used if necessary, as well as risk ratio (RR) and 95% confidence intervals (95CI). Correlation between AFI and perinatal outcomes was determined by using simple linear regression, and AFI progression during pregnancy was analyzed by Z-test. Results: When comparing newborns presenting ultrasound with AFI<5cm and AFI>5cm, there was a higher frequency of perinatal mortality when the AFI was lower than 5 cm. However, when the oligohydramnios was diagnosed as severe (AFI<3cm), there was a higher frequency of Apgar scores less than seven at 1 minute, neonatal sepsis and early neonatal mortality compared to those presenting AFI>3cm. There was a positive correlation between AFI and gestational age at delivery, birth weight and Apgar scores at minutes 1 and 5. There was also a decrease in amniotic fluid volume with increased gestational age. Conclusion: The presence of severe oligohydramnios after PPROM contributed to a higher frequency of perinatal complications and death.

RESUMO Objetivo: determinar a associação do índice de líquido amniótico (ILA) com os resultados perinatais na rotura prematura das membranas pré-termo (RPMPT). Método: realizou-se um estudo de coorte retrospectivo, de 2008 a 2012. Foram incluídas 86 gestantes, com diagnóstico de RPMPT e idade gestacional entre a 24ª e 35ª semanas. Foram excluídas gestantes que apresentavam síndromes hipertensivas, diabetes, fetos com malformações fetais e infecção na admissão. Para determinar a associação entre ILA e desfechos perinatais, foram utilizados os testes qui-quadrado e exato de Fisher, quando pertinentes, além da razão de risco (RR) e seu intervalo de confiança a 95% (IC95%). A correlação entre ILA e desfechos perinatais foi determinada por regressão linear simples, e a evolução do ILA durante a gestação foi analisada pelo teste Z. Resultados: quando comparados os recém-nascidos que apresentavam ultrassonografia com ILA<5 cm e ILA>5 cm, observou-se maior frequência de mortalidade perinatal nos casos de ILA<5 cm. Quando o oligo-hidrâmnio, porém, era diagnosticado como grave (ILA<3 cm), observava-se maior frequência de escore de Apgar <7 no 1º minuto, sepse neonatal e mortalidade neonatal precoce em relação aos que apresentavam ILA>3 cm. Observou-se uma correlação positiva entre ILA e idade gestacional no parto, peso ao nascer e escore de Apgar no 1º e 5º minutos, além de diminuição do volume do líquido amniótico com o avançar da idade gestacional. Conclusão: a presença de oligo-hidrâmnio grave após a RPMPT contribuiu para uma maior frequência de complicações e mortalidade perinatal.

The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited.

Rupture of the fetal membranes (FM) is precipitated by stretch forces acting upon biochemically mediated, pre-weakened tissue. Term FM develop a para-cervical weak zone, characterized by collagen remodeling and apoptosis, within which FM rupture is thought to initiate. Preterm FM also have a weak region but are stronger overall than term FM. Inflammation/infection and decidual bleeding/abruption are strongly associated with preterm premature FM rupture (pPROM), but the specific mechanisms causing FM weakening-rupture in pPROM are unknown. There are no animal models for study of FM weakening and rupture. Over a decade ago we developed equipment and methodology to test human FM strength and incorporated it into a FM explant system to create an in-vitro human FM weakening model system. Within this model TNF (modeling inflammation) and Thrombin (modeling bleeding) both weaken human FM with concomitant up regulation of MMP9 and cellular apoptosis, mimicking the characteristics of the spontaneous FM rupture site. The model has been enhanced so that test agents can be applied directionally to the choriodecidual side of the FM explant consistent with the in-vivo situation. With this enhanced system we have demonstrated that the pathways involving inflammation/TNF and bleeding/Thrombin induced FM weakening overlap. Furthermore GM-CSF production was demonstrated to be a critical common intermediate step in both the TNF and the Thrombin induced FM weakening pathways. This model system has also been used to test potential inhibitors of FM weakening and therefore pPROM. The dietary supplement α-lipoic acid and progestogens (P4, MPA and 17α-hydroxyprogesterone) have been shown to inhibit both TNF and Thrombin induced FM weakening. The progestogens act at multiple points by inhibiting both GM-CSF production and GM-CSF action. The use of a combined biomechanical/biochemical in-vitro human FM weakening model system has allowed the pathways of fetal membrane weakening to be delineated, and agents that may be of clinical use in inhibiting these pathways to be tested.

Maternal serum interleukin-6 in the management of patients with preterm premature rupture of membranes.

AIM: To evaluate the clinical usefulness of maternal serum interleukin-6 for the detection of subclinical chorioamnionitis and in the prediction of the latency period in patients with preterm premature rupture of membrane (PPROM). METHODS: The study group included 60 patients at 24-34 weeks of gestation complaining of PPROM. Laboratory investigations included serial measurements of IL-6, TLC and CRP. Conservative management was carried out till 36 weeks unless delivery was indicated beforehand. The main outcome measures were the latency period and the occurrence of subclinical chorioamnionitis. RESULTS: The mean gestational age at presentation was 30.9 weeks and 35.2 weeks at delivery. The mean IL-6 level at presentation was 4.7 pg/ml. There was no correlation between IL-6 at presentation and the latency period. In addition, those diagnosed as having subclinical chorioamnionitis by placental histopathology had significantly higher levels of IL-6 at delivery. Taking IL-6 level cutoff point of 8.5 pg/ml, histological chorioamnionitis, RDS and NICU admission were significantly higher above that level while neonatal birth weight, Apgar scores at one and five minutes were significantly lower. CONCLUSION: Maternal serum IL-6 at the time of PPROM has no correlation to the latency period while IL-6 levels at the time of delivery have significant correlation to the subclinical chorioamnionitis and neonatal outcome measures.

Preterm prelabor rupture of membranes and outcome of very-low-birth-weight infants in the German Neonatal Network.

OBJECTIVE: It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation. DESIGN: Observational, epidemiological study design. SETTING: Population-based cohort, German Neonatal Network (GNN). POPULATION: 6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth). METHODS: Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age. RESULTS: PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes. CONCLUSIONS: The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.

Related factors and adverse neonatal outcomes in women with preterm premature rupture of membranes complicated by histologic chorioamnionitis.

BACKGROUND: The aim of this study was to identify factors predicting histologic chorioamnionitis (HCA) in women with preterm premature rupture of membranes (PPROM). MATERIAL AND METHODS: We retrospectively enrolled 371 women diagnosed with PPROM at less than 34 weeks of gestation at the Second Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2012. HCA was diagnosed by placental histopathology in 70% of participants. Binary logistic regression was used to identify factors associated with HCA and neonatal outcomes. RESULTS: Patient age, rate of parity, tocolysis, cesarean section, serum C reactive protein (CRP) level at admission, white blood cell count, and latency duration did not significantly differ between the 2 groups. Binary logistic regression revealed that oligohydramnios at admission, gestational age at PPROM, and serum CRP >8 mg/L before delivery were significantly associated with HCA. Gestational age at delivery and birth weight were significantly lower in HCA patients than control patients. The rate of 1-min Apgar score <7, abnormal neonatal intracranial ultrasound findings, neonatal pneumonia, bronchopulmonary dysplasia, early-onset neonatal sepsis, and mortality were higher in HCA patients, but no significant difference was observed in the incidence of neonatal respiratory distress syndrome, necrotizing enterocolitis, hyperbilirubinemia, or hypoglycemia. CONCLUSIONS: Younger gestational age at time of PPROM, higher CRP level before delivery, and oligohydramnios at admission in women with PPROM are associated with HCA, and HCA is associated with some adverse neonatal outcomes.

Chemotactic activity of gestational tissues through late pregnancy, term labor, and RU486-induced preterm labor in Guinea pigs.

PROBLEM: Is increased leukocyte chemotactic activity (CA) from gestational tissues necessary for term or preterm labor in guinea pigs? METHOD OF STUDY: Tissue extracts were prepared from pregnant guinea pig decidua-myometrium, cervix, fetal membranes (amniochorion), and placenta during early third trimester (n = 8), term not in labor (TNL, n = 5), and term spontaneous labor (TL, n = 6), RU486-induced preterm labor (PTL, n = 6), or controls (cPTL, n = 5). Leukocyte CA was assessed using a modified Boyden chamber assay. Extract chemokine and maternal progesterone concentrations were quantified by enzyme immunoassay. RESULTS: Only the extracts from amniochorion demonstrated increased CA through late gestation and labor. In contrast, CA was decreased in extracts from amniochorion and cervix from animals after RU486-induced PTL. Maternal progesterone concentrations remained high in all groups. CONCLUSION: Leukocyte CA of intrauterine tissues is increased in term spontaneous labor. However, RU486-induced preterm labor occurs in the absence of increased CA.

Oligohydramnios in women with preterm prelabor rupture of membranes and adverse pregnancy and neonatal outcomes.

OBJECTIVE: To determine the association between the presence of oligohydramnios, determined as an amniotic fluid index ≤ 5 cm and the intra-amniotic inflammatory response, fetal inflammatory response and neonatal outcomes in actively managed preterm prelabor rupture of membranes (PPROM). METHODS: Women with singleton pregnancies complicated by PPROM at a gestational age of between 24+0 and 36+6 weeks were included in the study. Ultrasound assessments of the amniotic fluid index and evaluation of the amniotic fluid interleukin (IL)-6 levels were performed at admission. The umbilical cord blood IL-6 levels were evaluated after delivery. RESULTS: In total, 74 women were included. The women with oligohydramnios did not have different amniotic fluid IL-6 levels [with oligohydramnios: median 342 pg/mL, interquartile range (IQR) 110-1809 vs. without oligohydramnios: median 256 pg/mL, IQR 122-748; p = 0.71] or umbilical cord blood IL-6 levels (with oligohydramnios: median 8.2 pg/mL, IQR 3.8-146.9 vs. without oligohydramnios: median 5.9 pg/mL, IQR 2.1-27.9; p = 0.14) than those without oligohydramnios. No association between oligohydramnios and neonatal morbidity was found. A correlation between the amniotic fluid index and the interval from rupture of membranes to amniocentesis was observed (rho = -0.34; p = 0.003). CONCLUSION: The presence of oligohydramnios is not associated with an adverse outcome in actively managed PPROM in singleton pregnancies in the absence of other complications.

Latency after preterm prelabor rupture of the membranes: increased risk for periventricular leukomalacia.

OBJECTIVE: To identify the risk factors for cystic periventricular leukomalacia (cPVL) and their implications for deciding between immediate delivery and conservative management of preterm prelabor rupture of the membranes (pPROM). METHODS: The following risk factors were compared between cPVL infants and 6440 controls: chorioamnionitis, sex, gestational age (GA), birth weight, pPROM, and pPROM-delivery interval. Factor impact on cPVL risk and clinical decision-making was determined by multivariate logistic regression. RESULTS: Overall cPVL prevalence (n = 32) was 0.99/1000 births. All cPVL infants but one were born <34 weeks of gestation and were <2500 g; 56% had histological chorioamnionitis versus 1.1% of controls (OR 35.9; 95%-CI 12.6-102.7). Because chorioamnionitis is a postnatal diagnosis, logistic regression was performed with prenatally available factors: pPROM-delivery interval >48 hours (OR 9.0; 95%-CI 4.1-20.0), male gender (OR 3.2; 95%-CI 1.4-7.3). GA was not a risk factor if birth weight was included. Risk decreased with increasing fetal weight despite a prolonged pPROM-delivery interval. CONCLUSION: pPROM-delivery interval is the single most important prenatally available risk factor for the development of cPVL. Immediate delivery favors babies with chorioamnionitis but disfavors those with non infectious pPROM. In the absence of clinical chorioamnionitis fetal weight gain may offset the inflammatory risk of cPVL caused by a prolonged pPROM-delivery interval.

Volume de líquido amniótico e os desfechos maternos em gestantes com ruptura prematura das membranas pré-termo / Amniotic fluid volume and maternal outcomes in women with preterm premature rupture of membranes

OBJETIVO: Analisar entre pacientes com ruptura prematura de membranas pré-termo a associação do volume do líquido amniótico e os desfechos maternos. MÉTODOS: Estudo observacional do tipo coorte retrospectivo, realizado entre janeiro de 2008 e dezembro de 2012. Foram incluídas 86 gestantes com diagnóstico de ruptura prematura das membranas e idade gestacional entre a 24ªe a 35ª semanas, submetidas à mensuração do índice de líquido amniótico (ILA). Foram comparadas gestantes em dois pontos de cortes: com ILA <5,0 e ≥5,0 cm e ILA <3,0 e ≥3,0 cm. Foram excluídas mulheres com síndromes hipertensivas, diabetes mellitus, malformações fetais e com diagnóstico de infecção na admissão. Para análise estatística, foi utilizado o teste do χ2 ou exato de Fisher, quando pertinentes, e análise de regressão linear simples, adotando-se um nível de significância de 5%. Foi calculada a Razão de Risco (RR) e seu intervalo de confiança de 95% (IC95%). RESULTADOS: Quando avaliados os desfechos maternos em relação ao ILA ≥5,0 versus <5,0 cm, não foram encontradas diferenças estatisticamente significativas. Entretanto, em relação ao ILA <3,0 e ≥3,0 cm, foi verificado aumento do risco de corioamnionite (36,7 versus 10,7%; RR: 3,4; IC95% 1,4 -8,3; p=0,004), não sendo observadas diferenças significativas para as outras variáveis estudadas. Houve ainda correlação positiva estatisticamente significativa entre o ILA e idade gestacional do parto (R2=0,78; p<0,0001). CONCLUSÕES: O ILA <3,0 cm aumenta em três vezes o risco para corioamnionite, e quanto maior o ILA, maior a idade gestacional do parto. .

PURPOSE: To describe the potential influence of amniotic fluid on the maternal outcome of preterm premature rupture of membranes (PROM). METHODS: An observational, retrospective cohort study was conducted between December 2012 and January 2008 on 86 pregnant women with preterm PROM and a gestational age (GA) of 24 to 35 weeks. The amniotic fluid index (AFI) was used to measure aminiotic fluid volume. Pregnant women were compared at two cut-off points: those with AFI <5.0 and ≥5.0 cm and AFI <3.0 and ≥3.0 cm. We excluded women with hypertensive disorders, diabetes mellitus, fetal malformations and a diagnosis of infections at admission. For statistical analysis, we used the χ2 test or Fisher's exact test, when appropriate, and simple linear regression analysis, with the level of significance set at 5%. We calculated the Risk Ratio (RR) and its 95% confidence interval (95%CI). RESULTS: When maternal outcomes were assessed by comparing ILA ≥5.0 versus <5.0 cm, no significant differences were detected. However, when considering ILA <3.0 and ≥3.0 cm, there was an increased risk of chorioamnionitis (36.7 versus10.7%, RR: 3.4, 95%CI 1.4 -8.3, p=0.004), with no significant differences for the other variables. There was also a statistically significant positive correlation between AFI and gestational age at delivery (R2=0.78, p<0.0001). CONCLUSIONS: AFI <3.0 cm causes a three-fold increase in the risk for chorioamnionitis; also, the higher the ILA, the higher the gestational age at delivery. .