"Doing something" about the cesarean delivery rate.

There is a general consensus that the cesarean delivery rate in the United States is too high, and that practice patterns of obstetricians are largely to blame for this situation. In reality, the US cesarean delivery rate is the result of 3 forces largely beyond the control of the practicing clinician: patient expectations and misconceptions regarding the safety of labor, the medical-legal system, and limitations in technology. Efforts to "do something" about the cesarean delivery rate by promulgating practice directives that are marginally evidence-based or influenced by social pressures are both ineffective and potentially harmful. We examine both the recent American Congress of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine Care Consensus Statement "Safe Prevention of Primary Cesarean Delivery" document and the various iterations of the ACOG guidelines for vaginal birth after cesarean delivery in this context. Adherence to arbitrary time limits for active phase or second-stage arrest without incorporating other clinical factors into the decision-making process is unwise. In a similar manner, ever-changing practice standards for vaginal birth after cesarean driven by factors other than changing data are unlikely to be effective in lowering the cesarean delivery rate. Whether too high or too low, the current US cesarean delivery rate is the expected result of the unique demographic, geographic, and social forces driving it and is unlikely to change significantly given the limitations of current technology to otherwise satisfy the demands of these forces.

Can the optimal cervical length for placing ultrasound-indicated cerclage be identified?

OBJECTIVE: To assess a continuum of cervical length (CL) cut-offs for the efficacy of ultrasound-indicated cerclage in women with previous spontaneous preterm birth (PTB). METHODS: This was a planned secondary analysis of a multicenter randomized clinical trial of ultrasound-indicated cerclage for the prevention of PTB in high-risk women. The efficacy of cerclage for preventing recurrent PTB < 35, < 32 and < 24 weeks' gestation was assessed using multivariable logistic regression analysis. Odds ratios (ORs) and CIs were estimated for a range of CL cut-offs using bootstrap regression. The 2.5(th) and 97.5(th) percentiles of bootstrapped ORs determined the CIs. Results were illustrated using smoothed curves superimposed on estimated ORs by CL cut-off. RESULTS: Of 301 women with a CL < 25 mm, 142 underwent ultrasound-indicated cerclage and 159 did not have cerclage placement. The few cases with CL < 10 mm limited the evaluation to CL cut-offs between < 10 mm and < 25 mm. For PTB < 35 weeks, ORs in women with a cerclage and CL < 25 mm were statistically significantly lower than in those without cerclage, and efficacy was maintained at smaller CL cut-offs. Results were similar for PTB < 32 weeks. For PTB < 24 weeks, results differed, with ORs increasing toward unity (no benefit), with wide CIs, for CL cut-offs between < 10 mm and < 15 mm, attributed to the small number of births < 24 weeks. CONCLUSIONS: The efficacy of ultrasound-indicated cerclage in women with previous spontaneous PTB varies by action point CL cut-off and by PTB gestational age of interest. Cerclage significantly reduces the risk of PTB < 35 and < 32 weeks, at CL cut-offs between < 10 mm and < 25 mm, with the greatest reduction at shorter CL, affirming that women with prior spontaneous PTB and a short CL are appropriate candidates for ultrasound-indicated cerclage. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Reconsidering the switch from low-molecular-weight heparin to unfractionated heparin during pregnancy.

Venous thromboembolic disease accounts for 9% of all maternal deaths in the United States. In patients at risk for thrombosis, common practice is to start prophylactic doses of low-molecular-weight heparin and transition to unfractionated heparin during the third trimester, with the perception that administration of neuraxial anesthesia will be safer while on unfractionated heparin, as spinal/epidural hematomas have been associated with recent use of low-molecular-weight heparin. In patients receiving prophylactic doses of unfractionated heparin, neuraxial anesthesia may be placed, provided the dose used is 5,000 units twice a day. The American Society of Regional Anesthesia and Pain Medicine guidelines recognize that the safety of neuraxial anesthesia in patients receiving more than 10,000 units per day or more than 2 doses per day is unknown, limiting the theoretical benefit of unfractionated heparin at doses higher than 5,000 units twice a day.

M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity.

The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) functions in the intracellular trafficking of lysosomal enzymes, the activation of the potent growth inhibitor, transforming growth factor beta 2, and the degradation of IGF2 (ref. 1), a mitogen often overproduced in tumours. We have recently shown that 70% of human hepatocellular tumours have loss of heterozygosity (LOH) at the M6P/IGF2R locus which maps to chromosome 6q26-q27 (ref. 8). Using a coarse screen, we have now identified point mutations in the remaining allele of 25% of human hepatocellular carcinomas (HCCs) with LOH. These mutations give rise to truncated receptor protein and significant amino acid substitutions, and provide evidence that the M6P/IGF2R gene functions as a tumour suppressor in human liver carcinogenesis.

Characteristics of women with nausea and vomiting of pregnancy who chose to continue compassionate use of placebo after a randomised trial.

The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period.

Association between body mass index and pregnancy outcome in a randomized trial of cerclage for short cervix.

OBJECTIVE: To evaluate whether increasing body mass index (BMI) alters the efficacy of ultrasound-directed cerclage in women with a history of preterm birth. METHODS: This was a planned secondary analysis of a multicenter trial in which women with a singleton gestation and prior spontaneous preterm birth (17 to 33 + 6 weeks' gestation) were screened for a short cervix by serial transvaginal ultrasound evaluations between 16 and 22 + 6 weeks. Women with a short cervix (cervical length < 25 mm) were randomly assigned to cerclage or not. Linear and logistic regression were used to assess the relationship between BMI and continuous and categorical variables, respectively. RESULTS: Overall, in the screened women (n = 986), BMI was not associated with cervical length (P = 0.68), gestational age at delivery (P = 0.12) or birth at < 35 weeks (P = 0.68). For the cerclage group (n = 148), BMI had no significant effect. For the no-cerclage group (n = 153), BMI was associated with a decrease in gestational age at delivery, with an estimated slope of - 0.14 weeks per kg/m(2) (P = 0.03; including adjustment for cervical length). This result was driven primarily by several women with BMI > 47 kg/m(2) . CONCLUSION: In women at high risk for recurrent preterm birth, BMI was not associated with cervical length or gestational age at birth. BMI did not appear to adversely affect ultrasound-indicated cerclage.

Timing of mid-trimester cervical length shortening in high-risk women.

OBJECTIVE: To examine the natural history of cervical length shortening in women who had experienced at least one prior spontaneous preterm birth at between 17+0 and 33+6 weeks' gestation. METHODS: This was an analysis of prerandomization data from the multicenter Vaginal Ultrasound Cerclage Trial. Serial cervical length was measured by transvaginal sonography in 1014 high-risk women at 16+0 to 22+6 weeks. We performed survival analyses in which the outcome was cervical length shortening<25 mm and data were censored if this did not occur before 22+6 weeks' gestation. The incidence of cervical length shortening and the time to shortening were compared for women whose earliest prior preterm birth was in the mid-trimester, defined as <24 weeks, vs. those at weeks 24-33. Similar comparisons were performed based on each patient's most recent birth history. RESULTS: Time to cervical length shortening by survival analysis was significantly shorter (hazard ratio (HR)=2.2, P<0.0001) and the relative risk (RR) of shortening significantly higher (RR=1.8, P<0.0001) for women whose earliest prior spontaneous preterm birth was at <24 weeks. A larger effect was observed for women whose most recent birth was at <24 weeks (HR=2.8, P<0.0001; RR=2.1, P<0.0001). The observed hazard ratios remained significant after adjusting for confounders in a multivariable Cox proportional hazards model. CONCLUSION: Women with a prior spontaneous preterm birth at <24 weeks are at a higher risk of cervical shortening, and do so at a higher rate and at an earlier gestational age, than do women with a later preterm birth history.

Defining cerebral palsy: pathogenesis, pathophysiology and new intervention.

Cerebral palsy (CP) affects 2/1 000 live-born children. There are several antenatal factors, including preterm delivery, low birth weight, infection/inflammation, multiple gestations, and other pregnancy complications, that have been associated with CP in both the preterm and term infant, with birth asphyxia playing a minor role. Due to the increasing survival of the very preterm and very low birth weight infant secondary to improvements in neonatal and obstetric care, the incidence of CP may be increasing. The topics of neonatal encephalopathy and CP, as well as hypoxic-ischemic encephalopathy, are of vital importance to anyone who ventures to deliver infants. Criteria sufficient to define an acute intrapartum hypoxic event as sufficient to cause CP have been advanced previously by both the American College of Obstetricians and Gynecologists and the International Cerebral Palsy Task Force. This review will cover the progression toward defining the pathogenesis and pathophysiology of cerebral palsy. Four essential criteria were advanced as prerequisites if one is to propose that an intrapartum hypoxic-ischemic insult has caused a moderate to severe neonatal encephalopathy that subsequently results in CP. Importantly, all four criteria must be met: 1) evidence of metabolic acidosis (pH <7.0 and base deficit of 12 mmol/L or more); 2) early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks' gestation; 3) CP of the spastic quadriplegic or dyskinetic type, and 4) exclusion of other identifiable etiologies, such as trauma, coagulation disorders, infectious conditions, or genetic disorders. Other criteria that together suggest intrapartum timing are also discussed. The focus of this paper is to explore antenatal antecedents as etiologies of CP and the impact of obstetric care on the prevention of CP.

Newborn brachial plexus injuries: The twisting and extension of the fetal head as contributing causes.

The exact mechanism of the causation of brachial plexus injury (BPI) has long been a matter of controversy. It is our opinion that the twisting and the extension of the fetal head, during the labour and delivery process, will increase the stretching of the neck, thus contributing to the labour forces as the cause of BPI. Our opinions are offered to other researchers and readers for their consideration of how the labour forces can cause BPI.

Contrast sonography, video densitometry and intervillous blood flow: a pilot project.

PURPOSE: To examine the feasibility of constructing time-intensity (TI) curves from the intervillous space with an intravascular ultrasound contrast agent and computer assisted video densitometry. STUDY DESIGN: We sedated nine pregnant baboons, optimized the grey scale and color Doppler images of their placentas, and then fixed the transducers in place. For each injection of contrast, we recorded images on videotape without changing the ultrasound image processing functions. Video images were captured using a Macintosh personal computer equipped with a video-capture board using image analysis software (Image 1.4, W Rasband, NIH). For each injection, we sampled digitized images of a fixed region of interest at regular intervals. After computing the mean video density of each image, we used the sampling frequency to construct TI curves depicting any change over time as the contrast agents washed into and out of the intervillous space. RESULTS: Three of four agents tested produced changes in the video density of the placenta. TI curves were established using both grey scale and color Doppler signal augmentation. As expected, intra-arterial agents produced rapid accumulation and decay. Intravenous agents produced more protracted effects secondary to bolus dilution and transit through the right heart and pulmonary vascular bed. CONCLUSION: TI curves may be generated from the intervillous space with the use of a transpulmonary ultrasound contrast agent and video densitometry. If validated by further study, this may allow investigators to apply ultrasound and indicator-dilution theory to intervillous blood flow.

Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors.

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIr) is required for the activation of transforming growth factor beta, and previously we have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs). Therefore, we have postulated that loss of the M6P/IGFIIr gene may be mechanistically involved in liver carcinogenesis. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of the M6P/IGFIIr gene to screen non-cirrhotic, hepatitis virus negative patients with hepatocellular tumors for LOH. Twenty-two of 36 (61%) patients were informative (heterozygous), and 14/22 (64%) liver tumors had LOH; 11/16 (69%) carcinomas, 1/3 (33%) fibrolamellar tumors and 2/3 (67%) adenomas. This is the first report of LOH at the M6P/IGFIIr locus in human hepatocellular tumors, and the presence of LOH in adenomas suggests that allelic loss may be an early event in the etiology of HCCs. These results support the hypothesis that the M6P/IGFIIr gene may function as a tumor suppressor gene in the liver.

M6P/IGF2 receptor: a candidate breast tumor suppressor gene.

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) functions in the activation of TGFbeta, a potent growth inhibitor for most cell types, the degradation of the mitogen, IGF2, and the intracellular trafficking of lysosomal enzymes. We have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of heterozygosity (LOH) at this locus with mutations in the remaining allele in human liver tumors. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of M6P/IGF2r to screen breast tumors for LOH. Forty of 62 (65%) patients were informative (heterozygous) and 12/40 (30%) breast tumors had LOH; 5/19 (26%) carcinomas in situ (CIS) and 7/21 (33%) invasive carcinomas. To investigate the early molecular genetic events in breast carcinogenesis, we screened the CIS with LOH for mutations. In 2/5 (40%) of these tumors, missense mutations were found in the remaining allele that gave rise to significant amino acid substitutions. These findings provide evidence that M6P/IGF2r allelic loss is an early event in the etiology of breast cancer, that this gene functions as a tumor suppressor gene in the breast.

The genetic and molecular organization of the Dopa decarboxylase gene cluster of Drosophila melanogaster.

We report the complete molecular organization of the Dopa decarboxylase gene cluster. Mutagenesis screens recovered 77 new Df(2L)TW130 recessive lethal mutations. These new alleles combined with 263 previously isolated mutations in the cluster to define 18 essential genes. In addition, seven new deficiencies were isolated and characterized. Deficiency mapping, restriction fragment length polymorphism (RFLP) analysis and P-element-mediated germline transformation experiments determined the gene order for all 18 loci. Genomic and cDNA restriction endonuclease mapping, Northern blot analysis and DNA sequencing provided information on exact gene location, mRNA size and transcriptional direction for most of these loci. In addition, this analysis identified two transcription units that had not previously been identified by extensive mutagenesis screening. Most of the loci are contained within two dense subclusters. We discuss the effectiveness of mutagens and strategies used in our screens, the variable mutability of loci within the genome of Drosophila melanogaster, the cytological and molecular organization of the Ddc gene cluster, the validity of the one band-one gene hypothesis and a possible purpose for the clustering of genes in the Ddc region.

In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector.

Bone morphogenetic proteins (BMPs) are polypeptides that induce ectopic bone formation in standard rat in vivo assay systems. Previous studies have demonstrated the clinical utility of these proteins in spinal fusion, fracture healing, and prosthetic joint stabilization. Gene therapy is also a theoretically attractive technique to express BMPs clinically, since long-term, regulatable gene expression and systemic delivery with tissue-specific expression may be possible in future. This study was performed to determine whether an adenoviral vector containing the BMP-2 gene can be used to express BMP-2 in vitro and promote endochondral bone formation in vivo. In vitro, U87 MG cells transduced per cell with 20 MOI of an adenoviral construct containing the BMP-2 gene under the control of the universal CMV promoter (Ad-BMP-2) showed positive antibody staining for the BMP-2 protein at posttransfection day 2. The synthesis and secretion of active BMP-2 into the conditioned medium of Ad-BMP-2-transduced 293 cells were confirmed by Western blot analysis and the induction of alkaline phosphatase activity in a W-20 stromal cell assay. In vivo, Sprague-Dawley rats and athymic nude rats were injected with Ad-BMP-2 in the thigh musculature and were sacrificed on day 3, 6, 9, 12, 16, 21, 60, and 110 for histological analysis. The Sprague-Dawley rats showed evidence of acute inflammation, without ectopic bone formation, at the injection sites. In the athymic nude rats, BMP-2 gene therapy induced mesenchymal stem cell chemotaxis and proliferation, with subsequent differentiation to chondrocytes. The chondrocytes secreted a cartilaginous matrix, which then mineralized and was replaced by mature bone. This study demonstrates that a BMP-2 adenoviral vector can be utilized to produce BMP-2 by striated muscle cells in athymic nude rats, leading to endochondral bone formation. However, in immunocompetent animals the endochondral response is attenuated, secondary to the massive immune response elicited by the first-generation adenoviral construct.

Validation of the 1988 ACOG forceps classification system.

In February 1988, an ACOG Committee Opinion substantially revised the classification of forceps operations. The revision addressed two significant shortcomings of the old system: Outlet forceps had been defined too narrowly and midforceps too imprecisely. We now report the results of a prospective study of 357 forceps deliveries classified using each system. Allowing up to 45 degrees of rotation in an outlet forceps delivery did not increase morbidity measured by any criterion. Dividing the old midforceps group by precisely identifying station and rotation permitted greater stratification of the risks of short-term neonatal and maternal morbidity. We conclude that our results validate the 1988 classification scheme.

Uterine contraction pressures achieved in parturients with active phase arrest.

An adequate trial of labor preceding cesarean delivery for arrest of cervical dilatation in the active phase of labor has not been defined precisely. We reviewed the records of 85 consecutive women at term who received oxytocin for induction or augmentation of labor and who subsequently delivered by cesarean for arrest of labor in the active phase. The mean duration of oxytocin infusion was 15 hours for induction of labor and 8.9 hours for augmentation. Thirty-four (92%) of the 37 women who received oxytocin induction and 44 (92%) of the 48 who had oxytocin for augmentation achieved at least 200 Montevideo units of uterine pressure. All 85 newborns were vigorous at birth and had no complications during their stay in the hospital nursery. Evaluation of uterine contraction pressure can provide a quantifiable end point for the management of oxytocin induction or augmentation of labor.

Twins: prophylactic hospitalization and ward rest at early gestational age.

One hundred eighty-nine twin pregnancies were delivered at Wilford Hall United States Air Force Medical Center from July 1977 through December 1985. Among these, 57 were referred from distant bases and were excluded from further analysis. The remaining 132 pregnancies from our local population make up the study group. Sixty-seven women (51%) followed our advice to be hospitalized at or before 28 weeks' gestation for prophylactic ward rest. The remaining 65 women (49%) were not hospitalized until after 28 weeks' gestational age or until a pregnancy complication or labor occurred. Only three of 134 infants (2%) whose mothers were admitted died, versus 11 of 130 infants (8.5%) whose mothers were not admitted (P less than .03). The results suggest that prophylactic ward rest, implemented at or before 28 weeks' gestational age, may reduce perinatal mortality in this condition.

Maternal arterial desaturation with 15-methyl prostaglandin F2 alpha for uterine atony.

Over a six-month period, five women with severe uterine atony and postpartum hemorrhage developed marked maternal arterial oxygen desaturation within five to ten minutes of the administration of 15-methyl prostaglandin F2 alpha. The average fall from baseline was 10.4 +/- 5.4%, to a mean arterial oxygen saturation of 88.8 +/- 5.45%. The desaturation was accompanied by acute increases, averaging 20.7 +/- 5.9%, in the intrapulmonary shunt.

Human papillomavirus associated with poor healing of episiotomy repairs.

A retrospective case-control investigation was conducted for risk factors in 47 parturients whose episiotomies dehisced in the immediate postpartum period. Data were extracted from the inpatient, outpatient, and pathology records of each of these 47 patients, as well as from the same records for each of the next two patients who delivered with the same type and degree of episiotomy. No difference between subjects and controls was found for age, parity, or medical history. Except for human papillomavirus (HPV), past or present history of sexually transmitted diseases was not a risk factor. However, active lesions, history thereof, or subsequent development of infection with HPV was found in 14 of 47 patients (29.8%) who had episiotomy breakdown, compared with 13 of 94 women (13.8%) who did not experience this complication, a statistically significant difference (P less than .023). Eleven subjects (23.4%) and nine controls (9.6%) gave a history of smoking during pregnancy, also a statistically significant difference (P less than .026).

Myocardial infarction during pregnancy: a review.

In the present review the world literature on pregnancy complicated by myocardial infarction is summarized, and two additional cases are presented. It is apparent that the majority of pregnant women who have died after myocardial infarction did so at the time of initial infarction, and maternal mortality was greatest if the infarction was late in pregnancy. Moreover, delivery within two weeks of infarction was associated with increased mortality as was reinfarction during labor. These results suggest that the increasing cardiovascular stresses of late pregnancy, especially when intensified by parturition, seriously compromise women with ischemic heart disease. Efforts should therefore be made to limit myocardial oxygen demand/consumption throughout pregnancy, and particularly during parturition. Although principles of management can be generalized, these high risk patients require individualization of care by a multidisciplinary team of cardiologists, anesthesiologists, and obstetricians.