Postmarketing surveillance for human teratogenicity: a model approach.

BACKGROUND: Most congenital defects associated with prenatal exposures are notable for a pattern of major and minor malformations, rather than for a single major malformation. Thus, traditional epidemiological methods are not universally effective in identifying new teratogens. The purpose of this report is to outline a complementary approach that can be used in addition to other more established methods to provide the most comprehensive evaluation of prenatal exposures with respect to teratogenicity. METHODS: We describe a multicenter prospective cohort study design involving dysmorphological assessment of liveborn infants. This design uses the Organization of Teratology Information Services, a North American network of information providers who also collaborate for research purposes. Procedures for subject selection, methods for data collection, standard criteria for outcome classification, and the approach to analysis are detailed. RESULTS: The focused cohort study design allows for evaluation of a spectrum of adverse pregnancy outcomes ranging from spontaneous abortion to functional deficit. While sample sizes are typically inadequate to identify increased risks for single major malformations, the use of dysmorphological examinations to classify structural anomalies provides the unique advantage of screening for a pattern of malformation among exposed infants. CONCLUSIONS: As the known human teratogens are generally associated with patterns of structural defects, it is only when studies of this type are used in combination with more traditional methods that we can achieve an acceptable level of confidence regarding the risk or safety of specific exposures during pregnancy.

Fatal fetal outcome with the combined use of valsartan and atenolol.

OBJECTIVE: To report a case of anhydramnios, pulmonary hypoplasia, very small placenta, and fetal death in a pregnancy complicated by chronic hypertension and diabetes mellitus that had been treated through the first 24 weeks of gestation with valsartan and atenolol. CASE SUMMARY: A 40-year-old Hispanic woman with well-controlled chronic hypertension and diet-controlled type 2 diabetes mellitus was treated with valsartan and atenolol until pregnancy was diagnosed at 24 weeks' gestation. An ultrasound examination revealed normal fetal growth and anatomy but anhydramnios (amniotic fluid index 0). Valsartan was discontinued, and amniotic fluid volume normalized within two weeks. Intrauterine fetal death was documented at 33 weeks' gestation. Labor was induced, with the delivery of a stillbom female fetus with small, hypoplastic lungs (weight 41% of expected) and an extremely small, 148-g placenta (weight 48% of the 10th percentile for gestational age). DISCUSSION: The use of valsartan, a selective angiotensin II receptor antagonist (ARA), in human pregnancy has not been reported, but this class of agents would be expected to cause fetal toxicity similar to that observed with angiotensin-converting enzyme inhibitors. This toxicity includes reduced perfusion of the fetal kidneys, resulting in anuria, oligohydramnios, and subsequent pulmonary hypoplasia. The small hypoplastic lungs and very small placenta were probably a consequence of valsartan and atenolol combination therapy. CONCLUSIONS: Resolution of anhydramnios after discontinuing valsartan is evidence for ARA-induced fetal toxicity. The pulmonary hypoplasia observed in the stillbom infant was a direct result of the severe oligohydramnios. The cause of fetal death nine weeks later is uncertain, but because the woman's chronic hypertension and diabetes were well controlled, we believe the primary cause was chronic placental insufficiency resulting from the previous combination of valsartan and atenolol.

Medication use during the perinatal period.

OBJECTIVE: To briefly describe the drug therapy administered during the perinatal period of pregnancy for common maternal and fetal complications, and to identify those agents that should not be used for these conditions. DATA SOURCES: References were obtained from an ongoing literature search of peer-reviewed obstetric and gynecologic journals and other selected medical and pharmacy journals available in the English language. Primary search vehicle was a weekly review of the tables of contents of nearly 1,300 medical journals provided by Reference Update (Institute of Scientific Information, Philadelphia). MEDLINE searches were also conducted using key terms for each subtopic. STUDY SELECTION: Specific references were selected for each topic based on the adequacy of their study design, patient population, and a recent publication date. Reviews were used if a large number of primary references would have been required to adequately describe the topic. DATA EXTRACTION: Most references reflected the current opinions expressed in the Educational (Technical) Bulletin and Committee Opinion series published by the American College of Obstetricians and Gynecologists. Recent, well-conducted studies that arrived at different conclusions were also included. DATA SYNTHESIS: Data obtained from each reference reflected the conclusions of the authors based on their research or an analysis of the research on others on the appropriate use of the drug(s) for the specific condition being treated. CONCLUSION: Drug therapy during the perinatal period is frequently required and can be beneficial for the mother, fetus, and newborn. Many complications previously associated with severe morbidity and mortality, such as infections, premature rupture of membranes, preterm labor, hypertension, maternal pain during labor, and postpartum hemorrhage, are now controlled with appropriate pharmacologic therapy. All health professionals who provide services to pregnant women should be knowledgeable in this drug therapy.

Droperidol and diphenhydramine in the management of hyperemesis gravidarum.

OBJECTIVE: Hyperemesis gravidarum is a common pregnancy complication requiring hospitalization. Continuous droperidol infusion and bolus intravenous diphenhydramine were instituted as treatment. We compared the number and length of hospitalizations for hyperemesis gravidarum, readmissions for this diagnosis, and pregnancy outcome in patients receiving this treatment protocol with a historic group of patients receiving other forms of parenteral therapy for hyperemesis gravidarum. STUDY DESIGN: All patients hospitalized with a diagnosis of hyperemesis gravidarum between January 1992 and January 1994 were offered the droperidol-diphenhydramine protocol. These patients were compared with patients admitted between January 1990 and January 1992 with a diagnosis of hyperemesis gravidarum but who were not treated with droperidol at any time or with diphenhydramine as primary therapy for the control of severe nausea and vomiting. Data regarding the number and length of hospitalizations and readmissions for hyperemesis gravidarum were compared, as were maternal and perinatal outcomes. RESULTS: Patients treated with the droperidol-diphenhydramine protocol had significantly shorter hospitalizations (3.1 +/- 1.9 vs 3.8 +/- 2.4 days, p = 0.028), fewer days per pregnancy hospitalized for hyperemesis (3.5 +/- 2.3 days vs 4.8 +/- 4.3 days, p = 0.018), and fewer readmissions with this diagnosis (15.0% vs 31.5%, p = 0.015). There were no significant differences in maternal or perinatal outcomes. CONCLUSION: Droperidol and diphenhydramine infusion is a beneficial, cost-effective therapy for the treatment of hyperemesis gravidarum.

Excretion of bupropion in breast milk.

OBJECTIVE: To measure the excretion of bupropion and its metabolites in breast milk. A secondary objective was to determine whether the drug accumulated in the nursing infant. CASE SUMMARY: Milk and plasma samples were collected from a woman taking bupropion 300 mg/d in divided doses who was breastfeeding her 14-month-old son. A single plasma sample was collected from the infant. RESULTS: After a 100-mg dose, the peak bupropion breast milk concentration measured at two hours was 0.189 micrograms/mL. Milk-to-plasma ratios ranged from 2.51 to 8.58 over a six-hour interval. Two of three metabolites also were measured in milk. Bupropion and its metabolites were not detected in the single plasma sample obtained from the infant. CONCLUSIONS: Bupropion accumulates in human breast milk in concentrations much higher than in maternal plasma. Two metabolites are also excreted into the milk. Neither bupropion nor its metabolites were detected in the infant's plasma, indicating that accumulation did not occur in this infant.

A randomized, placebo-controlled trial of betamethasone for the prevention of respiratory distress syndrome at 24 to 28 weeks' gestation.

Previous randomized controlled studies of corticosteroids for the reduction of respiratory distress syndrome have failed to demonstrate benefit in very early premature gestational age groups. A randomized, double-blind, placebo-controlled clinical trial of betamethasone given to mothers with intact membranes and threatened premature delivery between 24 and 28 weeks of pregnancy was conducted. Thirty-six patients were randomized to receive betamethasone, two doses of 12 mg, 24 hours apart, and 41 received placebo. No difference was found in the overall incidence of respiratory distress syndrome between the two groups (betamethasone vs placebo 0.55 vs 0.66) or in the incidence of respiratory distress syndrome in babies delivered between 1 and 7 days after the first dose of drug (betamethasone vs placebo 0.78 vs 0.88). Nor were there any differences observed in any measure of severity of respiratory distress syndrome between the groups. The neonatal death rates were also similar (betamethasone vs placebo 0.25 vs 0.24). The only difference seen was an unexpected reduction in the betamethasone group in the incidence of grades 3 and 4 intraventricular hemorrhage (betamethasone vs placebo 1/31 vs 9/36, p = 0.01). Therefore this study was unable to demonstrate any beneficial effect of corticosteroids in reducing respiratory distress syndrome at less than 28 weeks' gestation in spite of a sample size that had an 80% likelihood of detecting a 50% reduction in the incidence of respiratory distress syndrome with p = 0.05, which is the minimum reduction seen in virtually all randomized trials in other gestational age groups.

Predicting the behaviour of pesticides in soil from their physical and chemical properties.

Increasingly stringent environmental requirements for pesticides mean that both biological activity and favourable environmental behaviour must be assessed at an early stage in pesticide discovery. Soil behaviour is governed by the physical properties of the molecule: partition coefficient, dissociation constant, vapour pressure and melting point, which control potential movement under particular soil and environmental conditions and the soil persistence. Established chemical structure-physical property correlations generally allow physical properties to be estimated for the large number of compounds in a synthesis programme with adequate precision. Stability to chemical or biological transformations in soil is more difficult to estimate but a combination of measurement for a few compounds and analogy with known chemical and biological transformation rates for various functional groups can give useful structure-stability correlations.

Simplified postoperative patient-controlled analgesia on a gynecologic oncology service.

Twenty-nine women who underwent various abdominal operations for gynecologic malignancies self-administered postoperative analgesia by means of disposable Travenol Infusors with Patient Control Modules. Administration of morphine sulfate at a rate of 1 mg per injection and a maximum of 10 mg per hour via patient-controlled analgesia was judged satisfactory by all 29 patients. The mean dose rate administered ranged from 1.2 to 1.5 mg per hour per day during the first 3 days postoperatively. No respiratory depression occurred and excessive sedation was reported by only 2 patients after the first 24 hr postoperatively. If further surgeries were required, more than 90% of these patients would prefer patient-controlled analgesia to intramuscular injections.

Gentamicin dosing in postpartum women with endometritis.

Postpartum women receiving gentamicin for endometritis were studied to determine if selective determination of gentamicin serum levels was cost-effective in terms of safety and efficacy. The women were randomized into two groups of 30 patients each. In the control group gentamicin serum levels were determined after the third dose. In the study group, levels were determined only if renal dysfunction was evident or if the patient failed to respond to therapy. Determination of serum levels did not assure a better therapeutic outcome in either group, as measured by hospital stay, duration of treatment, total cost of antibiotics, and hospital readmissions. Although pharmacokinetic dosing equations were used, the use of 1.75 mg/kg every 8 hours based on actual body weight in patients with average heights and weights would have produced acceptable results. We conclude that routine monitoring of gentamicin serum levels is not required in otherwise healthy postpartum women with endometritis.

Morphine: continuous intravenous infusion versus intramuscular injections for postoperative pain relief.

Postoperative pain was controlled in 42 patients with either continuous intravenous (iv) or scheduled intramuscular morphine following surgery for gynecologic cancers. In this double-blind study, no statistical differences were found in pain control or rate of complications between the two methods of administration. Both routes were effective in controlling pain without producing major toxicity. Initial doses were based on the patient's weight and then adjusted every 4 hr. We conclude that both methods are safe and effective but that continuous iv infusion is the preferred route because of the ease of administration, elimination of multiple intramuscular injections, and possibly more even pain control.

Obtaining drug exposure histories during pregnancy.

One hundred fifty-three pregnant patients were included in this study to verify the amount of drugs ingested during their pregnancies. The results demonstrate that, unknown to the physician, pregnant patients take a variety of pharmacologic agents. The patient's medical record is considered grossly inadequate in documenting an accurate assessment of a patient's exposure to drugs taken during pregnancy. Drug histories were obtained utilizing the hospital pharmacist drug history interview and home diary. Validity testing of the pharmacist's drug history and of the medical record history was not performed. The patient's compliance for utilizing the home diary for drugs or chemicals taken during their pregnancy was 83% (127 patients). It was shown that the usual methods of drug history documentation will identify only 30% of the actual drug exposure to the fetus.

Patterns of hand preference in a student population.

The handedness of 1599 college students was assessed using a modification of Annett's (1967) inventory. The addition of a strength of preference scale makes the "mixed" classification a better indicator of ambidexterity than in the original inventory by eliminating from it subjects who show preference for the same hand for nearly all tasks. Contrary to previous reports, sex was not significantly related to handedness. It was found that a family history of left-handedness was significantly related to the handedness of the subject. The present form of the Annett inventory provides an easily scorable inventory for determining handedness of large groups as well as for use in individual testing situations. A further advantage of the present inventory is the ease with which data may be transferred by key-punch operators prior to special analysis or sorting procedures.