The role of the placenta in spontaneous preterm labor and delivery with intact membranes.

OBJECTIVES: To determine whether placental vascular pathology and impaired placental exchange due to maturational defects are involved in the etiology of spontaneous preterm labor and delivery in cases without histologic acute chorioamnionitis. METHODS: This was a retrospective, observational study. Cases included pregnancies that resulted in spontaneous preterm labor and delivery (<37 weeks), whereas uncomplicated pregnancies that delivered fetuses at term (≥37-42 weeks of gestation) were selected as controls. Placental histological diagnoses were classified into three groups: lesions of maternal vascular malperfusion, lesions of fetal vascular malperfusion, and placental microvasculopathy, and the frequency of each type of lesion in cases and controls was compared. Moreover, we specifically searched for villous maturational abnormalities in cases and controls. Doppler velocimetry of the umbilical and uterine arteries were performed in a subset of patients. RESULTS: There were 184 cases and 2471 controls, of which 95 and 1178 had Doppler studies, respectively. The frequency of lesions of maternal vascular malperfusion was greater in the placentas of patients with preterm labor than in the control group [14.1% (26/184) vs. 8.8% (217/2471) (p=0.023)]. Disorders of villous maturation were more frequent in the group with preterm labor than in the control group: 41.1% (39/95) [delayed villous maturation in 31.6% (30/95) vs. 2.5% (13/519) in controls and accelerated villous maturation in 9.5% (9/95) vs. none in controls]. CONCLUSIONS: Maturational defects of placental villi were associated with approximately 41% of cases of unexplained spontaneous preterm labor and delivery without acute inflammatory lesions of the placenta and with delivery of appropriate-for-gestational-age fetuses.

Vindicating a traduced genius: Ignaz Philipp Semmelweis (1818-1865).

Anglophone narratives of Semmelweis's discovery of the cause and prophylaxis of childbed (puerperal) fever are based on a deficient historical record because important information about what happened to Semmelweis in Vienna, Austria, is contained in primary documents that had never been translated into English until very recently. The gaps in these narratives have been filled with invented facts and causal attributions that traduce Semmelweis by berating his character, education, and writing proficiency to hold him solely responsible for the rejection of his theory by most of his contemporaries and to explain the most puzzling aspect of his life: why he did not publish the results of his groundbreaking research in a medical journal for 11 years. This article presents the historical evidence contained in these primary documents that were missing from previous narratives and that provide very rational and understandable explanations for Semmelweis's actions. It also presents evidence that flatly contradicts the claims that have been made about Semmelweis's character, education, and writing skills and offers a more veridical portrayal of what happened to Semmelweis in Vienna that caused him to leave the city and delay publishing his results.

A Note on Semmelweis's Animal Experiments and Their Historical Significance.

This article seeks to establish what animal experiments Semmelweis conducted, and when and why he conducted them, because the Semmelweis literature contains conflicting claims about these topics or has ignored them altogether. Semmelweis first conducted animal experiments between 22 March and 20 August 1849 with Rokitansky's assistant, Georg Maria Lautner, because his chief, Johann Klein, did not accept that by merely reducing the mortality rate from childbed fever with chlorine hand-disinfection, Semmelweis had proved his theory of the cause of childbed fever. However, Skoda concluded that the Lautner experiments did not resolve the doubts about Semmelweis's theory they were intended to resolve, and, therefore, asked the Academy of Sciences to award Semmelweis a grant to conduct further and more varied experiments with the physiologist, Ernst Ritter von Brücke. These additional experiments were conducted in the spring and summer of 1850, but yielded only ambiguous results, and led Brücke to conclude that questions about Semmelweis's theory could only be resolved by clinical observations, not animal experiments. This article discusses the reasoning behind these animal experiments, and Skoda's and Brücke's responses to them, and argues that their responses to the experiments caused Semmelweis to delay publishing his research until he had collected sufficient clinical evidence to prove his theory.

Why Semmelweis's doctrine was rejected: evidence from the first publication of his results by Friedrich Wieger, and an editorial commenting on the results.

We present English translations of two French documents to show that the main reason for the rejection of Semmelweis's theory of the cause of childbed (puerperal) fever was because his proof relied on the post hoc ergo propter hoc fallacy, and not because Joseph Skoda referred only to cadaveric particles as the cause in his lecture to the Academy of Science on Semmelweis's discovery. Friedrich Wieger (1821-1890), an obstetrician from Strasbourg, published an accurate account of Semmelweis's theory six months before Skoda's lecture, and reported a case in which the causative agent originated from a source other than cadavers. Wieger also presented data showing that chlorine hand disinfection reduced the annual maternal mortality rate from childbed fever (MMR) from more than 7 per cent for the years 1840-1846 to 1.27 per cent in 1848, the first full year in which chlorine hand disinfection was practised. But an editorial in the Gazette médicale de Paris rejected the data as proof of the effectiveness of chlorine hand disinfection, stating that the fact that the MMR fell after chlorine hand disinfection was implemented did not mean that this innovation had caused the MMR to fall. This previously unrecognized objection to Semmelweis's proof was also the reason why Semmelweis's chief rejected Semmelweis's evidence.

Rediscovering Ignaz Philipp Semmelweis (1818-1865).

Ignaz Philipp Semmelweis was a Hungarian obstetrician who discovered the cause of puerperal or childbed fever (CBF) in 1847 when he was a 29-year-old Chief Resident ("first assistant") in the first clinic of the lying-in division of the Vienna General Hospital. Childbed fever was then the leading cause of maternal mortality, and so ravaged lying-in hospitals that they often had to be closed. The maternal mortality rate (MMR) from CBF at the first clinic where Semmelweis worked, and where only medical students were taught, was 3 times greater than at the second clinic, where only midwives were taught, and Semmelweis was determined to find out why. Semmelweis concluded that none of the purported causes of CBF could explain the difference in MMR between the 2 clinics, as they all affected both clinics equally. The clue to the real cause came after Semmelweis' beloved professor, Jacob Kolletschka, died after a student accidentally pricked Kolletscka's finger during an autopsy. Semmelweis reviewed Kolletschka's autopsy report, and noted that the findings were identical to those in mothers dying of CBF. He then made 2 groundbreaking inferences: that Kolletschka must have died of the same disease as mothers dying of CBF, and that the cause of CBF must be the same as the cause of Kolletschka's death, because if the 2 diseases were the same, they must have the same cause. Semmelweis quickly realized why the MMR from CBF was higher on the first clinic: medical students, who assisted at autopsies, were transferring the causative agent from cadavers to the birth canal of mothers in labor with their hands, and he soon discovered that it could also be transferred from living persons with purulent infections. Bacteria had not yet been discovered to cause infections, and Semmelweis called the agent "decaying animal organic matter." He implemented chlorine hand disinfection to remove this organic matter from the hands of the attendants, as soap and water alone had been ineffective. Hand disinfection reduced the MMR from CBF 3- to 10-fold, yet most leading obstetricians rejected Semmelweis' doctrine because it conflicted with all extant theories of the cause of CBF. His work was also used in the fight raging over academic freedom in the University of Vienna Medical School, which turned Semmelweis chief against him, and forced Semmelweis to return to Budapest, where he was equally successful in reducing MMR from CBF. But Semmelweis never received the recognition that his groundbreaking work deserved, and died an ignominious death in 1865 at the age of 47 in an asylum, where he was beaten by his attendants and died of his injuries. Fifteen years later, his work was validated by the adoption of the germ theory, and honors were belatedly showered on Semmelweis from all over the world; but over the last 40 years, a myth has been created that has tarnished Semmelweis' reputation by blaming the rejection of his work on Semmelweis' character flaws. This myth is shown to be a genre of reality fiction that is inconsistent with historical facts.

Mechanisms of death in structurally normal stillbirths.

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

Peer review of medical practices: missed opportunities to learn.

Appropriately conducted peer review of medical practices provides the greatest opportunity for health care professionals to learn from their mistakes and improve the quality and safety of health care. But in practice, peer review has not been an effective learning tool because it is subjective and irreproducible. Physicians reviewing the same cases disagree over the cause(s) of adverse outcomes and the quality and appropriateness of care, and agreement is not improved by training, use of objective review criteria, or having the reviewers discuss the cases. The underlying reason is a general lack of understanding and an oversimplified view of the causes of medical errors in complex, high-risk organization and a preoccupation with attributing medical errors to particular individuals. This approach leads to judgments, not understanding, and creates a culture of blame that stops learning and undermines the potential for improvement. For peer review to have an impact on the quality of care and patient safety, it must be standardized to remove cognitive biases and subjectivity from the process.

The diagnostic performance of the Mass Restricted (MR) score in the identification of microbial invasion of the amniotic cavity or intra-amniotic inflammation is not superior to amniotic fluid interleukin-6.

OBJECTIVE: Intra-amniotic infection/inflammation are major causes of spontaneous preterm labor and delivery. However, diagnosis of intra-amniotic infection is challenging because most are subclinical and amniotic fluid (AF) cultures take several days before results are available. Several tests have been proposed for the rapid diagnosis of microbial invasion of the amniotic cavity (MIAC) or intra-amniotic inflammation. The aim of this study was to examine the diagnostic performance of the AF Mass Restricted (MR) score in comparison with interleukin-6 (IL-6) and matrix metalloproteinase-8 (MMP-8) for the identification of MIAC or inflammation. METHODS: AF samples were collected from patients with singleton gestations and symptoms of preterm labor (n = 100). Intra-amniotic inflammation was defined as >100 white blood cells/mm(3) (WBCs) in AF; MIAC was defined as a positive AF culture. AF IL-6 and MMP-8 were determined using ELISA. The MR score was obtained using the Surface-Enhanced Laser Desorption Ionization Time of Flight (SELDI-TOF) mass spectrometry. Sensitivity and specificity were calculated and logistic regression models were fit to construct receiver-operating characteristic (ROC) curves for the identification of each outcome. The McNemar's test and paired sample non-parametric statistical techniques were used to test for differences in diagnostic performance metrics. RESULTS: (1) The prevalence of MIAC and intra-amniotic inflammation was 34% (34/100) and 40% (40/100), respectively; (2) there were no significant differences in sensitivity of the three tests under study (MR score, IL-6 or MMP-8) in the identification of either MIAC or intra-amniotic inflammation (using the following cutoffs: MR score >2, IL-6 >11.4 ng/mL, and MMP-8 >23 ng/mL); (3) there was no significant difference in the sensitivity among the three tests for the same outcomes when the false positive rate was fixed at 15%; (4) the specificity for IL-6 was not significantly different from that of the MR score in identifying either MIAC or intra-amniotic inflammation when using previously reported thresholds; and (5) there were no significant differences in the area under the ROC curve when comparing the MR score, IL-6 or MMP-8 in the identification of these outcomes. CONCLUSIONS: IL-6 and the MR score have equivalent diagnostic performance in the identification of MIAC or intra-amniotic inflammation. Selection from among these three tests (MR score, IL-6 and MMP-8) for diagnostic purposes should be based on factors such as availability, reproducibility, and cost. The MR score requires a protein chip and a SELDI-TOF instrument which are not widely available or considered "state of the art". In contrast, immunoassays for IL-6 can be performed in the majority of clinical laboratories.

Systemic bias in peer review: suggested causes, potential remedies.

OBJECTIVE: The aim of this study was to determine if peer review conducted under real-world conditions is systematically biased. STUDY DESIGN: A repeated-measures design was effectively created when two board-certified obstetrician-gynecologists reviewed the same 26 medical records of patients treated by the same physician, and provided written evaluations of each case and a summary of their criticisms. The reviews were conducted independently for two different, unaffiliated hospitals. Neither reviewer was aware of the other's review, and neither was affiliated with either hospital or knew the physician under review. This study reports the degree of agreement between the two reviewers over the care rendered to these 26 patients. RESULTS: Three of the 26 cases reviewed had complications. Both reviewers criticized these cases, but criticized 2 of them for different reasons. At least one of the reviewers criticized 14 (61%) of the 23 uncomplicated cases, about which no quality concerns had been raised prior to the review. With one exception, they criticized completely different cases and criticized this 1 case for different reasons. Thus, only 4 of the 17 cases criticized by at least one of the reviewers were criticized by both of them, and only 1 of the 4 cases were criticized for the same reason. The Kappa statistic was -0.024, indicating no agreement between the reviewers (P = 0.98). CONCLUSIONS: As presently conducted, peer review can be systematically biased even when conducted independently by external reviewers. Dual-process theory of reasoning can account for the bias and predicts how the bias may potentially be eliminated or reduced.

Maternal death following cardiopulmonary collapse after delivery: amniotic fluid embolism or septic shock due to intrauterine infection?

PROBLEM: The amniotic fluid embolism (AFE) syndrome is a catastrophic complication of pregnancy frequently associated with maternal death. The causes and mechanisms of disease responsible for this syndrome remain elusive. METHOD OF STUDY: We report two cases of maternal deaths attributed to AFE: (1) one woman presented with spontaneous labor at term, developed intrapartum fever, and after delivery had sudden cardiovascular collapse and disseminated intravascular coagulation (DIC), leading to death; (2) another woman presented with preterm labor and foul-smelling amniotic fluid, underwent a Cesarean section for fetal distress, and also had postpartum cardiovascular collapse and DIC, leading to death. RESULTS: Of major importance is that in both cases, the maternal plasma concentration of tumor necrosis factor-alpha at the time of admission to the hospital and when patients had no clinical evidence of infection was in the lethal range (a lethal range is considered to be above 0.1 ng/mL). CONCLUSION: We propose that subclinical intraamniotic infection may be a cause of postpartum cardiovascular collapse and DIC and resemble AFE. Thus, some patients with the clinical diagnosis of AFE may have infection/systemic inflammation as a mechanism of disease. These observations have implications for the understanding of the mechanisms of disease of patients who develop cardiovascular collapse and DIC, frequently attributed to AFE. It may be possible to identify a subset of patients who have biochemical and immunological evidence of systemic inflammation at the time of admission, and before a catastrophic event occurs.