Alan M. Golichowski

TOCOLYTIC THERAPY: A META-ANALYSIS AND DECISION ANALYSIS

OBJECTIVE: To determine the optimal first-line tocolytic agent for treatment of premature labor. METHODS: We performed a quantitative analysis of randomized controlled trials of tocolysis, extracting data on maternal and neonatal outcomes, and pooling rates for each outcome across trials by treatment. Outcomes were delay of delivery for 48 hours, 7 days, and until 37 weeks; adverse effects causing discontinuation of therapy; absence of respiratory distress syndrome; and neonatal survival. We used weighted proportions from a random-effects meta-analysis in a decision model to determine the optimal first-line tocolytic therapy. Sensitivity analysis was performed using the standard errors of the weighted proportions. RESULTS: Fifty-eight studies satisfied the inclusion criteria. A random-effects meta-analysis showed that all tocolytic agents were superior to placebo or control groups at delaying delivery both for at least 48 hours (53% for placebo compared with 75–93% for tocolytics) and 7 days (39% for placebo compared with 61–78% for tocolytics). No statistically significant differences were found for the other outcomes, including the neonatal outcomes of respiratory distress and neonatal survival. The decision model demonstrated that prostaglandin inhibitors provided the best combination of tolerance and delayed delivery. In a hypothetical cohort of 1,000 women receiving prostaglandin inhibitors, only 80 would deliver within 48 hours, compared with 182 for the next-best treatment. CONCLUSION: Although all current tocolytic agents were superior to no treatment at delaying delivery for both 48 hours and 7 days, prostaglandin inhibitors were superior to the other agents and may be considered the optimal first-line agent before 32 weeks of gestation to delay delivery.

Gestational diabetes: should it be added to the syndrome of insulin resistance?

OBJECTIVE The significance of gestational diabetes mellitus (GDM) results from its short-term detrimental effects on the fetus and its long-term prediction of NIDDM in the mother. We compared several variables associated with insulin resistance between GDM and non-GDM pregnant women to show the similarities between GDM and NIDDM (and thus insulin resistance). RESEARCH DESIGN AND METHODS On the basis of a 3-h oral glucose tolerance test (OGTT), 52 GDM patients and 127 non-GDM patients were recruited from pregnant, non-diabetic women who had a nonfasting 1-h-50-g glucose screening test ≥ 7.2 mmol/l (130 mg/dl) performed between 16 and 33 weeks of gestation (a total of 518 of 3,041 women drawn from six community health care prenatal clinics were screened positive). During the OGTT, several potential markers of insulin resistance were measured at fasting and 2-h time points, in addition to the standard glucose measurements. The relationship of these variables with the diagnosis of GDM was studied. RESULTS GDM patients, compared with non-GDM patients, had 1) higher prepregnancy weight (P = 0.011), prepregnancy BMI (P = 0.006), C-peptide at fasting (P = 0.002) and at 2 h (P < 0.001), insulin at fasting (P = 0.001) and at 2 h (P < 0.001), triglycerides at fasting (P = 0.005) and at 2 h (P = 0.003), free fatty acids at fasting (P = 0.017), β-hydroxybutyrate at fasting (P = 0.007); and 2) lower HDL cholesterol at fasting (P = 0.029). These variables were all predictive of GDM (P < 0.036) individually. Using stepwise logistic regression with all of these variables available, fasting (P = 0.019) and 2-h (P < 0.001) insulin levels, fasting free fatty acids (P = 0.031), and fasting β-hydroxybutyrate (P = 0.036) were statistically significant as jointly predictive of GDM. Comparisons between GDM patients and non-GDM patients matched by BMI confirmed that the metabolic abnormalities persisted when difference in BMI was taken into account. Concomitant blood pressure measurements in women with GDM did not differ significantly from those without GDM. CONCLUSIONS Our results show that many of the known metabolic components of the syndrome of insulin resistance (syndrome X) are predictive of GDM. These results are in keeping with the argument that GDM is one phase of the syndrome of insulin resistance. We suggest that GDM be looked upon as a component of the syndrome of insulin resistance that provides an excellent model for the study and prevention of NIDDM in a relatively young age-group.

Tocolytic and hemodynamic effects of nifedipine in the ewe

The ability of the calcium antagonist nifedipine to inhibit uterine contractions during labor and in the postpartum period was measured in the ewe. The hemodynamic effects of tocolytic doses of this drug were measured and compared with the hemodynamic effects of equivalent doses of ritodrine. Intravenous nifedipine was found to be a potent tocolytic agent that completely inhibited uterine activity even in advanced labor when administered at infusion rates that resulted in only mild hemodynamic effects. At tocolytically similar infusion rates nifedipine produced significantly less increase in maternal heart rate than did ritodrine.

Insulin-Like Growth Factors I and II Peptide and Messenger RNA Levels in Macrosomic Infants of Diabetic Pregnancies

Objective: Fetal macrosomia is a common complication of maternal diabetes mellitus and is associated with substantial morbidity, but the precise cellular and molecular mechanisms that induce fetal macrosomia are not well understood. We hypothesized that the macrosomia or accelerated fetal growth seen in infants of diabetic mothers is due to a perturbation of a putative placental-fetal growth axis involving growth hormone and insulin-like growth factors. Insulin-like growth factors I and II (IGF-I and IGF-II) are ubiquitous peptides that share structural homology with insulin and have been implicated in processes that control fetal growth. Studies of IGF levels in pregnancies complicated by diabetes and macrosomia have shown conflicting results. We set out to resolve these inconsistencies using molecular techniques to measure the placental IGF-I and IGF-II messenger RNA levels in placentas and a specific radioimmunoassay to measure IGF-I and IGF-II peptide levels in cord serum of normal and diabetic pregnancies. Methods: Placentas and cord blood were collected immediately after delivery at term from patients from each of three study groups: 1) nonmacrosomic infants of nondiabetic mothers (controls), 2) macrosomic infants of diabetic mothers, and 3) nonmacrosomic infants of diabetic mothers. Both IGF-I and IGF-II levels were measured in cord serum and placental tissue by a specific radioimmunoassay. Total RNA was extracted and analyzed by Northern gels hybridized to IGF-I or IGF-II riboprobes. Results: Levels of IGF-I in cord serum from the macrosomic diabetic group (83 ± 4.2 ng/mL) were significantly higher than levels from either the nonmacrosomic nondiabetic group (38 ± 1.9 ng/mL) or the nonmacrosomic diabetic group (13 ± 3.5 ng/mL). There was a direct linear correlation between cord serum IGF-I and infant birth weight, independent of diabetes (r2 = 0.61, P < .01). On the other hand, IGF-II cord serum levels were elevated in diabetic pregnancies (337 ± 12.2 ng/mL) compared with nondiabetic women (172 ± 19.8 ng/mL), but there was no correlation with birth weight (r2 = 0.035, P = .52). In contrast to cord blood levels, IGF-II peptide levels were significantly decreased in the placentas from mothers with diabetes compared with nondiabetic controls (116 ± 3.2 versus 158 ± 5.3 ng/mL, respectively). Levels of IGF-I peptide in placentas from both nondiabetic controls and diabetic mothers were below the sensitivity of the assay. levels of IGF-I and IGF-II mRNA did not differ in placentas from diabetic mothers versus nondiabetic controls. Conclusion: Cord serum IGF-II levels are elevated in diabetic pregnancies without a concomitant increase in placental IGF-II levels. This novel finding, combined with the finding that IGF-I levels are correlated with macrosomia independent of the diabetic state, contributes to our understanding of the possible mechanisms involved in fetal growth in pregnancies complicated by diabetes.

Prenatal ultrasound detection of isolated neural tube defects: is cytogenetic evaluation warranted?

Objective To determine the value of cytogenetic evaluation in fetuses with isolated neural tube defects diagnosed by prenatal ultrasound. Methods Fifty-five thousand two hundred sixty obstetric ultrasounds performed for various indications at the Indiana University Prenatal Diagnostic Center from July 1988 to March 1994 were reviewed using a computerized data base. Excluding all cases of anencephaly, fetuses with isolated neural tube defects were identified. Maternal demographic data, pregnancy outcomes, level of defect, and fetal karyotype when available were obtained. Statistical analysis was performed using the χ2 test, when appropriate. P ≤ .05 was considered statistically significant. Results Seventy-seven medical record charts of women with prenatally diagnosed isolated fetal neural tube defects were reviewed. Nineteen pregnancies were terminated, 42 pregnancies were delivered, and 16 pregnancies were lost to follow-up. Karyotypes were available in 43 of the 77 cases (55.8%). The theoretical risk of chromosomal anomalies in this sample population based solely on maternal age was 0.3%. Of the 43 documented karyotypes, seven chromosomal anomalies were discovered (16.3%). The difference was statistically significant (P = .012). Detected chromosomal anomalies included two trisomy 18, two triploid 69, XXX, one triploid 69, XXY, one balanced Robertsonian translocation t(13q14q), and one inversion in the q arm of the X chromosome. Conclusion The prevalence of karyotypic abnormalities is significantly increased in fetuses with isolated neural tube defects; therefore, prompt antenatal genetic evaluation should be considered in such cases.

Gestational diabetes mellitus and gene mutations which affect insulin secretion.

We investigated whether genetic mutations known to impair insulin secretion and glucose tolerance are operative in a group of American women with gestational diabetes mellitus. Study groups were comprised of elderly non-diabetic controls (n = 55) with normal glucose tolerance and patients with gestational diabetes (n = 50), together with one family with maturity-onset diabetes of the young (three controls and three affected). No mutations were detected in any exon of the human glucokinase gene or the mitochondrial tRNA[Leu](UUR) gene by single strand conformational analysis and direct exon sequencing. Also, chi2 analysis showed no significant association with gestational diabetes for a polymorphism at position -30 (G --> A) of the beta-cell-specific glucokinase gene promoter. We have determined that glucokinase and mitochondrial tRNA[Leu](UUR) gene mutations, which are known to impair insulin secretion are relatively uncommon and do not constitute a large component of genetic risk for gestational diabetes in the study population.

Respiratory distress following elective repeat cesarean section

The clinical course and chest radiographs of 47 infants with respiratory distress after elective cesarean section were reviewed. The mean difference between the gestational age determined prenatally and that postnatally was 2.6 +/- 1.6 weeks. However, 14 of the infants were delivered at term. All 47 infants required more than 40% oxygen, and 18 infants required a respirator. Fifteen infants developed a pneumothorax; one, a pneumopericardium; one, bronchopulmonary dysplasia; and one infant died. Chest radiographs and the clinical course were consistent with hyaline membrane disease in 17 patients; respiratory distress syndrome type II in 24; and in three the radiographic findings were normal. These data suggest that some of the respiratory morbidity subsequent to elective repeat cesarean section is not secondary to iatrogenic delivery of a premature infant, and that much of it is not due to hyaline membrane disease. These data emphasize that respiratory distress in an infant delivered by elective cesarean section does not necessarily suggest poor prenatal care in regard to the timing of delivery.

Pregnancy-associated aplastic anemia--report of 3 cases.

Abstract:  3 patients with pregnancy‐associated aplastic anemia are reported. Management throughout most of the pregnancy consisted of supportive care. In 2 patients an improvement in blood counts occurred after delivery and, in 1 of these, the pancytopenia recurred during a subsequent pregnancy. In 1 case no improvement occurred after delivery and the patient ultimately required an allogeneic bone marrow transplantation. The outcome of these 3 cases demonstrates that pregnancy‐associated aplastic anemia can be managed successfully. The improvement that often occurs after delivery suggests a pathogenetic role for pregnancy in the development of this disease.

Pregnancy associated with lupus anticoagulant and heparin induced thrombocytopenia: management with a low molecular weight heparinoid

The management of pregnant patients with coagulopathies and heparin induced thrombocytopenia is difficult and poorly defined. We report the case of a patient who was treated with a low molecular weight heparinoid. The treatment was complicated by the delayed occurrence of thrombocytopenia and a thrombotic event. This is the first report of thrombocytopenia caused by heparinoid. It is possible that this complication could have been avoided by a shorter duration of treatment with heparinoid and the use of Vitamin K antagonists during the second trimester of pregnancy.

Controlled terminology for clinically-relevant indexing and selective retrieval of biomedical images

Existing clinical nomenclatures do not provide comprehensive, detailed coverage for multispecialty biomedical imaging. To address clinical needs in this area, the College of American Pathologists (CAP), secretariat of the Systematized Nomenclature of Human and Veterinary Medicine (SNOMED), has entered into partnership with the DICOM (Digital Imaging and Communications in Medicine) Standards Committee, the American College of Radiology, the American Dental Association, the American Academy of Ophthalmology, the American Society for Gastrointestinal Endoscopy, the American Academy of Neurology, the American Veterinary Medical Association, and other professional specialty organizations to develop the controlled terminology that is needed for diagnostic imaging applications. Terminology development is coordinated with ongoing development and maintenance of the DICOM Standard. SNOMED content is being enhanced in two general areas: 1) imaging procedure descriptions and 2) diagnostic observations. The SNOMED DICOM Microglossary (SDM) has been developed to provide context-dependent value sets (SDM Context Groups) for DICOM codedentry data elements and semantic content specifications (SDM Templates) for reports and other structures composed of multiple data elements. The capability of storing explicitlylabeled coded descriptors from the SDM in DICOM images and reports improves the potential for selective retrieval of images and related information. A pilot test of distributed multispecialty terminology development using a World Wide Web (WWW) application was performed in 1997, demonstrating the feasibility of large-scale distributed development of SDM