Errol R. Norwitz

Birth weight as a predictor of brachial plexus injury

Objective To examine the relationship between birth weight and brachial plexus injury and estimate the number of cesareans needed to reduce such injuries. Methods All 80 neonatal records coded for brachial plexus injury from October 1985 to September 1993 at the Brigham and Womens Hospital in Boston, Massachusetts, were studied along with linked maternal files. Birth weight, method of delivery, presence or absence of shoulder dystocia, and any diagnosis of maternal gestational or nongestational diabetes were abstracted. Data for the group with brachial plexus injury were compared with data for live-born infants without this injury during the same period. The sensitivity and specificity of birth weight as a predictor of brachial plexus injury were calculated. Further, the number of cesarean deliveries necessary to prevent a single brachial plexus injury was estimated using various weight cutoffs (4000, 4500, and 5000 g) for elective cesarean delivery. Results Among 77,616 consecutive deliveries, there were 80 brachial plexus injuries identified, for an incidence of 1.03 per 1000 live births. The incidence of brachial plexus injury increased with increasing birth weight, operative vaginal delivery, and the presence of glucose intolerance. In the group of women without diabetes, between 19 and 162 cesarean deliveries would have been necessary to prevent a single immediate brachial plexus injury. Among women with diabetes, between five and 48 additional cesareans would have been required. Conclusion Although birth weight is a predictor of brachial plexus injury, the number of cesarean deliveries necessary to prevent a single injury is high at most birth weights. Because of the large number of cesarean deliveries needed to prevent a single brachial plexus injury in infants born to women without diabetes, it is difficult to recommend routine cesarean delivery for suspected macrosomia in these women.

Proteomic Profiling of the Amniotic Fluid to Detect Inflammation, Infection, and Neonatal Sepsis

Background Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score. Methods and Findings We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with “severe” amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with “no” (MR score of 0) inflammation or even “minimal” (MR score of 1 or 2) inflammation (median [range] MR 3–4: 0.4 d [0.0–49.6 d] versus MR 1–2: 3.8 d [0.0–151.2 d] versus MR 0: 17.0 d [0.1–94.3 d], p < 0.001). Nonetheless, a “minimal” degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3–4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture). Conclusions High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.

Impact of a comprehensive patient safety strategy on obstetric adverse events

OBJECTIVE We implemented a comprehensive strategy to track and reduce adverse events. STUDY DESIGN We incrementally introduced multiple patient safety interventions from September 2004 through November 2006 at a university-based obstetrics service. This initiative included outside expert review, protocol standardization, the creation of a patient safety nurse position and patient safety committee, and training in team skills and fetal heart monitoring interpretation. We prospectively tracked 10 obstetrics-specific outcome. The Adverse Outcome Index, an expression of the number of deliveries with at least 1 of the 10 adverse outcomes per total deliveries, was analyzed for trend. RESULTS Our interventions significantly reduced the Adverse Outcome Index (linear regression, r(2) = 0.50; P = .01) (overall mean, 2.50%). Concurrent with these improvements, we saw clinically significant improvements in safety climate as measured by validated safety attitude surveys. CONCLUSION A systematic strategy to decrease obstetric adverse events can have a significant impact on patient safety.

Acute complications of preeclampsia

Preeclampsia is an idiopathic multisystem disorder specific to human pregnancy and the puerperium. More precisely, it is a disease of the placenta, because it has also been described in pregnancies where there is trophoblast but no fetal tissue (complete molar pregnancies). Although the pathophysiology of preeclampsia is poorly understood, it is clear that the blueprint for its development is laid down early in pregnancy. It has been suggested that the pathologic hallmark is a complete or partial failure of the second wave of trophoblast invasion from 16 to 20 weeks’ gestation, which is responsible in normal pregnancies for destruction of the muscularis layer of the spiral arterioles. As pregnancy progresses, the metabolic demands of the fetoplacental unit increase. However, because of the abnormally shallow invasion of the placenta, the spiral arterioles are unable to dilate to accommodate the required increase in blood flow, resulting in “placental dysfunction” that manifests clinically as preeclampsia. Although attractive, this hypothesis remains to be validated. Preeclampsia is a clinical diagnosis. The classic definition of preeclampsia encompasses three elements: new-onset hypertension (defined as a sustained sitting blood pressure !140/90 mm Hg in a previously normotensive woman); new-onset proteinuria (defined as >300 mg/24 hours or !2+ on a clean-catch urinalysis in the absence of urinary tract infection); and new-onset significant nondependent edema. However, more recent consensus reports have suggested eliminating edema as a criterion for the diagnosis. A more extensive synopsis of preeclampsia is beyond the scope of this discussion. This monograph serves to review in detail the diagnosis and management of several acute maternal complications of preeclampsia: eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, liver rupture, pulmonary edema, renal failure, disseminated intravascular coagulopathy (DIC), hypertensive emergency, and hypertensive encephalopathy and cortical blindness. Correspondence: Errol R. Norwitz, MD, PhD, Department of Obstetrics & Gynecology, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail: enorwitz@partners.org PROD. # GRF20214

An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

Post-term induction of labor revisited.

Post-term pregnancy (longer than 42 weeks or 294 days) occurs in approximately 10% of all singleton gestations. The adverse outcomes of post-term pregnancy include a substantial increase in perinatal mortality and morbidity. ACOG currently recommends induction of labor for low-risk pregnancy during the 43rd week of gestation. However, that recommendation dates from 1989. Recent reports mandate reconsideration of the management of post-term pregnancy, including reinterpretation of the statistical risk of stillbirth in post-term pregnancies using ongoing (undelivered) rather than delivered pregnancies as the denominator, which shows a far higher risk to post-term fetuses than believed. Recent data also suggest that the risk of cesarean delivery after induction of labor at term is lower than reported, possibly because of improvements in methods for cervical ripening. Those findings provide rationale for earlier labor induction in low-risk pregnancies.

Progesterone Receptors in the Human Pregnancy Uterus Do they Hold the Key to Birth Timing

The process and timing of human parturition involves a complex hormonal dialogue between maternal and fetal systems that transforms the uterine muscle into the laboring state. Progesterone, through specific progesterone receptors (PRs) in uterine tissues, is key player in this process. For most of pregnancy, progesterone promotes myometrial relaxation and its withdrawal initiates parturition. In women, a functional progesterone withdrawal occurs by changes in PR isoform expression and/or function in myometrial cells. Research in the last 10 to 20 years has shown that progesterone actions are mediated by a variety of PRs including the classic nuclear PRs, PR-A and PR-B that mediate genomic actions, and a family of membrane-bound PRs that mediate non-genomic actions. Herein, we review current understanding of the PRs expressed in the human pregnancy uterus, the pathways through which they mediate progesterone actions, and their roles in controlling myometrial contractility and the parturition process.

Identification and Characterization of the Gonadotropin-releasing Hormone Response Elements in the Mouse Gonadotropin-releasing Hormone Receptor Gene

The response of the pituitary gonadotrope to gonadotropin-releasing hormone (GnRH) correlates directly with the concentration of GnRH receptors (GnRHR) on the cell surface, which is mediated in part at the level of GnRHR gene expression. Several hormones have been implicated in this regulation, most notably GnRH itself. Despite these observations and the central role that GnRH is known to play in reproductive development and function, the molecular mechanism(s) by which GnRH regulates transcription of the GnRHR gene has not been well elucidated. Previous studies in this laboratory have identified and partially characterized the promoter region of the mouse GnRHR gene and demonstrated that the regulatory elements for tissue-specific expression as well as for GnRH regulation are present within the 1.2-kilobase 5′-flanking sequence. By using deletion and mutational analysis as well as functional transfection studies in the murine gonadotrope-derived αT3-1 cell line, we have localized GnRH responsiveness of the mouse GnRHR gene to two DNA sequences at −276/−269 (designated Sequence UnderlyingResponsiveness to GnRH-2 (SURG-2), which contains the consensus sequence for the activating protein-1-binding site) and −292/−285 (a novel element designated SURG-1), and demonstrated that this response is mediated via protein kinase C. By using the electrophoretic mobility shift assay, we further demonstrate that a member(s) of the Fos/Jun heterodimer superfamily is responsible in part for the DNA-protein complexes formed on SURG-2, using αT3-1 nuclear extracts. These data define a bipartite GnRH response element in the mouse GnRHR 5′-flanking sequence and suggest that the activating protein-1 complex plays a central role in conferring GnRH responsiveness to the murine GnRHR gene.

Episiotomy, operative vaginal delivery, and significant perineal trauma in nulliparous women

OBJECTIVES The aim of this study was to determine whether choice of obstetric instrument at operative vaginal delivery is associated with any differences in the rate of significant perineal trauma and whether this rate is modified by the use of episiotomy. STUDY DESIGN The occurrence of significant perineal trauma among 323 consecutive operative vaginal deliveries was evaluated according to type of instrument used and performance of episiotomy. These findings were compared with spontaneous vaginal deliveries during the same period. RESULTS Among forceps deliveries the use of episiotomy was not associated with a difference in the occurrence of significant perineal trauma (55% vs 46%; relative risk, 1.2; 95% confidence interval, 0.8-1.9). Among vacuum extraction deliveries an increased rate of such trauma was noted when episiotomy was used (34.9% vs 9. 4%; relative risk, 3.7; 95% confidence interval, 1.2-11.2). There was no difference in the rate of significant perineal trauma according to type of forceps used. In a logistic regression analysis forceps delivery with or without episiotomy was associated with an increase of >10-fold in the rate of significant perineal trauma with respect to vacuum extraction deliveries without episiotomy. CONCLUSIONS Our data suggest that in forceps delivery neither the type of forceps nor episiotomy influences the risk of significant perineal trauma. When vacuum extraction delivery is performed, the use of episiotomy is associated with a higher risk of significant perineal trauma.

Measurement of Placental Alpha- Microglobulin-1 in Cervicovaginal Discharge to Diagnose Rupture of Membranes

OBJECTIVE: To compare the accuracy of an immunoassay to measure levels of placental alpha-microglobulin-1 in cervicovaginal secretions with that of conventional clinical assessment for the diagnosis of rupture of membranes. METHODS: A prospective observational study was performed in consecutive patients with signs or symptoms of rupture of membranes at Seoul National University Hospital from March 2005 to February 2006. Initial evaluation included both the standard clinical evaluation for rupture of membranes and placental alpha-microglobulin-1 immunoassay. Rupture of membranes was diagnosed if fluid was seen leaking from the cervical os or if two of the following three conditions were present: pooling of fluid, positive nitrazine test, or ferning. Rupture of membranes was diagnosed definitively on review of the medical records after delivery. RESULTS: Of 184 patients (11–42 weeks of gestation), rupture of membranes was diagnosed at initial presentation in 76% (139 of 184) using conventional clinical assessment and 88% (161 of 184) using placental alpha-microglobulin-1 immunoassay. Follow-up confirmed that a total of 159 of 183 patients (87%) had rupture of membranes at their initial presentations. Using this longitudinal assessment as the clinical gold standard, placental alpha-microglobulin-1 immunoassay confirmed rupture of membranes at initial presentation with a sensitivity of 98.7% (157 of 159), specificity of 87.5% (21 of 24), positive predictive value of 98.1% (157 of 160), and negative predictive value of 91.3% (21 of 23). Placental alpha-microglobulin-1 immunoassay was better than both the conventional clinical assessment and the nitrazine test alone in confirming the diagnosis of rupture of membranes. CONCLUSION: Measurement of placental alpha-microglobulin-1 in cervicovaginal secretions is superior to conventional clinical assessment in the diagnosis of rupture of membranes. LEVEL OF EVIDENCE: II