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Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65–70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor. [ABSTRACT FROM AUTHOR]

Problem To determine whether amniotic fluid ( AF) CXCL10 concentration is associated with histologic chronic chorioamnionitis in patients with preterm labor ( PTL) and preterm prelabor rupture of the membranes ( PROM). Method of Study This study included 168 women who had an episode of PTL or preterm PROM. AF interleukin (IL)-6 and CXCL10 concentrations were determined by immunoassay. Results (i) Increased AF CXCL10 concentration was associated with chronic ( OR: 4.8; 95% CI: 1.7-14), but not acute chorioamnionitis; (ii) increased AF IL-6 concentration was associated with acute ( OR: 4.2; 95% CI: 1.3-13.7) but not chronic chorioamnionitis; and (iii) an increase in AF CXCL10 concentration was associated with placental lesions consistent with maternal anti-fetal rejection ( OR: 3.7; 95% CI: 1.3-10.4). (iv) All patients with elevated AF CXCL10 and IL-6 delivered preterm. Conclusion Increased AF CXCL10 concentration is associated with chronic chorioamnionitis or maternal anti-fetal rejection, whereas increased AF IL-6 concentration is associated with acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Background: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known.Objective: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion.Study Design: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion.Results: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions.Conclusion: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. [ABSTRACT FROM AUTHOR]

Objective: Acute atherosis is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. However, the frequency of acute atherosis in the great obstetrical syndromes is unknown. The purpose of this study was to determine the frequency and topographic distribution of acute atherosis in placentas and placental bed biopsy samples obtained from women with normal pregnancy and those affected by the "great obstetrical syndromes". We also examined the relationship between acute atherosis and pregnancy outcome in patients with preeclampsia.Material and Methods: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women's Hospital/Detroit Medical Center was conducted to examine 16, 345 placentas. Patients were classified into the following groups: (1) uncomplicated pregnancy; (2) spontaneous preterm labor (sPTL) and preterm prelabor rupture of membranes (PPROM); (3) preeclampsia; (4) gestational hypertension; (5) small-for-gestational age (SGA); (6) chronic hypertension; (5) fetal death; (6) spontaneous abortion and (7) others. A subset of patients had placental bed biopsy. The incidence of acute atherosis was compared among the different groups.Results: (1) The prevalence of acute atherosis in uncomplicated pregnancies was 0.4% (29/6961) based upon examination of nearly 7000 placentas; (2) the frequency of acute atherosis was 10.2% (181/1779) in preeclampsia, 9% (26/292) in fetal death, 2.5% (3/120) in midtrimester spontaneous abortion, 1.7% (22/1,298) in SGA neonates and 1.2% (23/1,841) in sPTL and PPROM; (3) among patients with preeclampsia, those with acute atherosis than in those without the lesion had significantly more severe disease, earlier onset, and a greater frequency of SGA neonates (p < 0.05 all) and (4) the lesion was more frequently observed in the decidua (parietalis or basalis) than in the decidual segment of the spiral arteries in patients with placental bed biopsies.Conclusions: Acute atherosis is rare in normal pregnancy, and occurs more frequently in patients with pregnancy complications, including preeclampsia, sPTL, preterm PROM, midtrimester spontaneous abortion, fetal death and SGA. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to: (1) determine the amniotic fluid (AF) microbiology of patients with preterm prelabor rupture of membranes (PROM); and (2) examine the relationship between intra-amniotic inflammation with and without microorganisms (sterile inflammation) and adverse pregnancy outcomes in patients with preterm PROM. Methods: AF samples obtained from 59 women with preterm PROM were analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital mycoplasmas) and with broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). AF concentration of interleukin-6 (IL-6) was determined using ELISA. Results of both tests were correlated with AF IL-6 concentrations and the occurrence of adverse obstetrical/perinatal outcomes. Results: (1) PCR/ESI-MS, AF culture, and the combination of these two tests each identified microorganisms in 36% (21/59), 24% (14/59) and 41% (24/59) of women with preterm PROM, respectively; (2) the most frequent microorganisms found in the amniotic cavity wereSneathiaspecies andUreaplasma urealyticum; (3) the frequency of microbial-associated and sterile intra-amniotic inflammation was overall similar [ 29% (17/59)]: however, the prevalence of each differed according to the gestational age when PROM occurred; (4) the earlier the gestational age at preterm PROM, the higher the frequency of both microbial-associated and sterile intra-amniotic inflammation; (5) the intensity of the intra-amniotic inflammatory response against microorganisms is stronger when preterm PROM occurs early in pregnancy; and (6) the frequency of acute placental inflammation (histologic chorioamnionitis and/or funisitis) was significantly higher in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [93.3% (14/15) versus 38% (6/16);p = 0.001]. Conclusions: (1) The frequency of microorganisms in preterm PROM is 40% using both cultivation techniques and PCR/ESI-MS; (2) PCR/ESI-MS identified microorganisms in the AF of 50% more women with preterm PROM than AF culture; and (3) sterile intra-amniotic inflammation was present in 29% of these patients, and it was as or more common than microbial-associated intra-amniotic inflammation among those presenting after, but not before, 24 weeks of gestation. [ABSTRACT FROM AUTHOR]

Objective. Increased amniotic fluid concentrations of anti-microbial peptides, components of the innate immune system, have been reported in patients with preterm labor (PTL) with intact membranes and intra-amniotic infection and/or inflammation (IAI), as well as in patients with preterm prelabor rupture of the membranes (PPROM). This study was designed to confirm these results using a targeted approach, detecting DEFA1, DEFB1, GNLY, and S100A9 gene expression in the choriamniotic membranes in pregnancies complicated with PTL and intact membranes or PPROM, with and without histologic chorioamnionitis. Study design. Human fetal membranes were obtained from patients in the following groups: (1) PTL with intact membranes ( n = 15); (2) PTL with intact membranes with histologic chorioamnionitis ( n = 12); (3) PPROM ( n = 17); and (4) PPROM with histologic chorioamnionitis ( n = 21). The mRNA expression of α-defensin-1, β-defensin-1, calgranulin B and granulysin in the fetal membranes was determined by qRT-PCR. Results. (1) The expression of α-defensin-1 mRNA in the fetal membranes was higher in patients with PTL and intact membranes with histologic chorioamnionitis, than those without chorioamnionitis (19.4-fold, p < 0.001); (2) Among patients with histologic chorioamnionitis, patients with PTL and intact membranes had a higher α-defensin-1 mRNA expression than those with PPROM (5.5-fold, p = 0.003); (3) Histologic chorioamnionitis was associated with a higher calgranulin B mRNA expression in the chorioamniotic membranes of patients with both PTL and intact membranes (7.9-fold, p = 0.03) and PPROM (7.6-fold, p < 0.0001); (4) The expression of calgranulin B mRNA in the fetal membranes was higher in patients with PTL and intact membranes without histologic chorioamnionitis than in those with PPROM without histologic chorioamnionitis (2.7-fold, p = 0.03); (5) There were no differences in the expression of β-defensin-1 and granulysin in the chorioamniotic membranes between the study groups even in the presence of histologic chorioamnioniotis. Conclusions. (1) Among patients with histologic chorioamnionitis, the mRNA expression of α-defensin-1 and calgranulin B in the fetal membranes of patients with PTL and intact membranes as well as that of calgranulin B in the fetal membranes of patients with PPROM is higher than in the membranes of those without histologic chorioamnionitis; (2) histologic chorioamnionitis is associated with differences in the pattern of α-defensin-1 mRNA expression in the fetal membranes in patients with PTL and intact membranes and those with PPROM. [ABSTRACT FROM AUTHOR]

Objective. Human parturition is characterized by the activation of genes involved in acute inflammatory responses in the fetal membranes. Manganese superoxide dismutase (Mn SOD) is a mitochondrial enzyme that scavenges reactive oxygen species (ROS). Mn SOD is up-regulated in sites of inflammation and has an important role in the down-regulation of acute inflammatory processes. Therefore, the aim of this study was to determine the differences in Mn SOD mRNA expression in the fetal membranes in patients with term and preterm labor (PTL) as well as in acute chorioamnionitis. Study design. Fetal membranes were obtained from patients in the following groups: (1) term not in labor (n = 29); (2) term in labor (n = 29); (3) spontaneous PTL with intact mebranes (n = 16); (4) PTL with histological chorioamnionitis (n = 12); (5) preterm prelabor rupture of the membranes (PPROM; n = 17); and (6) PPROM with histological chorioamnionitis (n = 21). Mn SOD mRNA expression in the membranes was determined by quantitative real-time reverse transcription-polymerase chain reaction. Results. (1) Mn SOD mRNA expression was higher in the fetal membranes of patients at term in labor than those not in labor (2.4-fold; p = 0.02); (2) the amount of Mn SOD mRNA in the fetal membranes was higher in PTL than in term labor or in PPROM (7.2-fold, p = 0.03; 3.2-fold, p = 0.03, respectively); (3) Mn SOD mRNA expression was higher when histological chorioamnionitis was present both among patients with PPROM (3.8-fold, p = 0.02) and with PTL (5.4-fold, p = 0.02) than in patients with these conditions without histological chorioamnionitis; (4) expression of Mn SOD mRNA was higher in PTL with chorioamnionitis than in PPROM with chorioamnionitis (4.3-fold, p = 0.03). Conclusion. The increase in Mn SOD mRNA expression by fetal membranes in term labor and in histological chorioamnionitis in PTL and PPROM suggests that the fetus deploys anti-oxidant mechanisms to constrain the inflammatory processes in the chorioamniotic membranes. [ABSTRACT FROM AUTHOR]

Objective. Antibiotic administration has become part of the standard of care for patients with preterm premature rupture of membranes (PROM). Yet, the natural history of intrauterine infection/inflammation during antibiotic therapy remains largely unknown. This study was conducted to determine if antibiotic administration to the mother eradicates intra-amniotic infection and/or reduces the frequency of intra-amniotic inflammation, a risk factor for impending preterm labor/delivery and adverse neonatal outcome. Methods. A subset of patients with preterm PROM admitted to our institution underwent amniocenteses before and after antibiotic administration in order to guide clinical management. Amniotic fluid analysis consisted of a Gram stain, culture for aerobic and anaerobic bacteria as well as genital mycoplasmas, and amniotic fluid white blood cell (WBC) count. Microbial invasion of the amniotic cavity (MIAC) was defined as a positive amniotic fluid culture. Intra-amniotic inflammation was defined as an amniotic fluid WBC count ≥100/mm³. Patients were given antibiotics and steroids after the 24th week of gestation. Antibiotic treatment consisted of ampicillin and erythromycin for 7 days for patients without evidence of intra-amniotic inflammation or MIAC, and ceftriaxone, clindamycin and erythromycin for 10–14 days for those with intra-amniotic inflammation or MIAC. Results. Forty-six patients with preterm PROM whose first amniocentesis was performed between 18 and 32 weeks (median 27.4 weeks) were included in the study. The overall prevalence of intra-amniotic inflammation in the first amniocentesis was 39% (18/46). Seven had a positive amniotic fluid culture for microorganisms. At the time of the second amniocentesis, six of the seven patients with a positive amniotic fluid culture had microorganisms. Of 18 patients with intra-amniotic inflammation at admission, only three showed no evidence of inflammation after antibiotic treatment. Among patients with no evidence of intra-amniotic inflammation at admission, 32% (9/28) developed inflammation despite therapy. Five of these nine patients had positive amniotic fluid cultures. Conclusions. (1) Antibiotic administration (ceftriaxone, clindamycin, and erythromycin) rarely eradicates intra-amniotic infection in patients with preterm PROM; (2) intra-amniotic inflammation developed in one-third of patients who did not have inflammation at admission, despite antibiotic administration; (3) a sub-group of patients with documented inflammation of the amniotic cavity demonstrated a decrease in the intensity of the inflammatory process after antibiotic administration. [ABSTRACT FROM AUTHOR]

Objective: Patients with an episode of preterm labor that subsides in response to tocolysis and who, subsequently, deliver at term are considered to have false preterm labor. However, the episode of “preterm labor” may represent the uterine response (ie, uterine contractions) to an insult not severe enough to trigger preterm parturition, but which may put the fetus at risk for additional pregnancy complications, including growth restriction. The objective of this study was to compare the frequency of small-for-gestational-age (SGA) neonates among patients with an episode of increased uterine contractility who delivered at term and those who delivered preterm. Study Design: This retrospective cohort study included 849 patients. Inclusion criteria were (1) regular uterine contractions that required hospitalization, (2) intact membranes, and (3) gestational age between 20 and 36 weeks. SGA was defined as a birth weight of <10th percentile for gestational age. Placental pathologic evidence was reviewed, and the results were used to classify patients into an inflammatory cluster, vascular cluster, or both. Contingency tables, Mann-Whitney U test, and multivariate logistic regression were used for statistical analyses. A probability value of <.05 was considered significant. Results: The prevalence of SGA neonates in the study population was 16.1% (124/772). Patients who delivered at term had a significantly higher frequency of SGA neonates than those who delivered preterm (21.5% [64/298] vs 12.7% [60/474]; P = .001); the results of placental pathologic evidence were available in 63.7% (492/772) of the patients. Patients who delivered at term had a higher frequency of fetal or maternal vascular lesions without histologic evidence of inflammation than those who delivered preterm (29.1 % [43/148] vs 18.9% [65/344]; P = .01). Term delivery after an episode of regular preterm uterine contractions was associated with an odds ratio of 2.22 (95% CI, 1.28-3.85) to deliver an SGA neonate after the statistics were controlled for confounding variables. A subanalysis limited to patients who received tocolysis showed similar results. Conclusion: Patients with an episode of increased uterine contractility that subsided and who deliver at term are at risk for delivering an SGA neonate, which suggests that an episode of false preterm labor is not a benign condition. We propose that insults to the fetoplacental unit may be resolved by either irreversible preterm parturition or restriction of fetal growth. [Copyright &y& Elsevier]