A needed information source.

Most sources of information regarding drugs in pregnancy include information on whether a drug causes congenital anomalies and whether a drug causes changes in fetal function or neonatal adaptation. Therapeutic issues related to the treatment of maternal disease are not readily available. Despite known physiologic changes of pregnancy, drug dosages are widely assumed to be the same as the healthy adult. An informational source is needed which addresses the therapeutic issues of pregnant women.

Physiologic changes in pregnancy and their effect on drug disposition.

Changes in maternal physiology occur normally during pregnancy and have the potential to alter the absorption, distribution, and elimination of drugs used therapeutically in pregnant women. These physiologic changes include: plasma volume expansion and increases in extracellular fluid space and total body water; decreased plasma albumin concentration; a compensated respiratory alkalosis; increased cardiac output with regional blood flow changes; increased renal blood flow associated with increased glomerular filtration; changes in hepatic drug metabolizing enzymes; and changes in gastrointestinal function. These changes begin in early gestation but are most pronounced in the third trimester of pregnancy. Further maternal physiologic changes occur intrapartum with some normalizing themselves within 24 hours of delivery, while others are sustained only returning to normal some 12 weeks postpartum. These physiologic changes form the basis for the need for pharmacokinetic studies during pregnancy.

A randomized trial of misoprostol versus extra-amniotic sodium chloride infusion with oxytocin for induction of labor.

OBJECTIVE: Our purpose was to compare the efficacy and safety of misoprostol and extra-amniotic sodium chloride infusion with oxytocin for induction of labor. STUDY DESIGN: This randomized trial compared two methods of labor induction in women requiring cervical ripening. One hundred twenty-three women undergoing labor induction with a Bishop score < or =5 were randomly selected to receive either misoprostol, 50 microg intravaginally every 4 hours, or extra-amniotic sodium chloride infusion. The primary outcome variable was the time interval from induction to vaginal delivery. RESULTS: Sixty-one women received extra-amniotic sodium chloride infusion and 62 women received misoprostol. The mean time interval from the start of induction to vaginal delivery was 15.0 +/- 5.0 hours and 16.5 +/- 7.2 hours for the extra-amniotic infusion and misoprostol groups, respectively (P, not significant). The cesarean delivery rate was not significantly different between the 2 groups (32.8% for the extra-amniotic infusion group; 19.4% for the misoprostol group). Maternal and neonatal outcomes were similar between the 2 groups. CONCLUSIONS: Both methods of induction are equally efficacious and result in similar maternal and neonatal outcomes.

Placenta previa: a 22-year analysis.

OBJECTIVE: Our purpose was to identify what anesthetic method is safer for women with a placenta previa. STUDY DESIGN: We retrospectively reviewed all women with placenta previa who underwent cesarean delivery during the period January 1, 1976-December 31, 1997 at Northwestern Memorial Hospital. RESULTS: Of 93,384 deliveries, placenta previa was found in 514 women. Identifiable trends with time included an increasing incidence of placenta previa (r = 0.54, P <.01); cesarean hysterectomy (r = 0.54, P <.01); placenta accreta (r = 0.45, P <.03); and regional anesthesia (r = 0.84, P <.0001). The mean gestational age at delivery was 35.3 +/- 3.4 weeks and did not change with time. General anesthesia was used for delivery in 380 women and regional anesthesia was used for 134 women. Prior cesarean delivery and general anesthesia were independent predictors of the need for blood transfusion, but only prior cesarean delivery was a predictor of the need for hysterectomy. General anesthesia increased the estimated blood loss, was associated with a lower postoperative hemoglobin concentration, and increased the need for blood transfusion. Elective and emergent deliveries did not differ in estimated blood loss, in postoperative hemoglobin concentrations, or in the incidence of intraoperative and anesthesia complications. Regional and general anesthesia did not differ in the incidence of intraoperative and anesthesia complications. CONCLUSIONS: In women with placenta previa, general anesthesia increased intraoperative blood loss and the need for blood transfusion. Regional anesthesia appears to be a safe alternative.

Fetal heart rate characteristics at 25 to 28 weeks' gestation.

The objective of this article is to define normative fetal heart rate (FHR) tracing characteristics between 25-28 weeks' gestation in a low-risk population with normal pregnancy outcomes and to determine which criteria best determine FHR reactivity. Continuous FHR tracings were reviewed from 188 low-risk women participating in a trial of the Mammary Stimulation Test (MST) at 25-28 weeks' gestation. A reactive tracing required the presence of > or =two accelerations in 20 min. Different acceleration criteria were evaluated based upon the width of the acceleration (short vs. long) and the amplitude of the acceleration (10 vs. 15 bpm). Seventy-one percent of the FHR tracings were reactive using the higher amplitude (15 bpm), short criteria. This number increased significantly to 92% when the lower amplitude (10 bpm), short criteria were used (p <0.01). As gestational age advanced, there was a trend toward increased reactivity irrespective of which criteria were used, but these differences were not significant. Reducing the acceleration amplitude criteria to 10 bpm in preterm pregnancies will maximize the number of reactive nonstress tests. This is advantageous because it would improve test specificity and decrease the false-positive rate. Our findings need to be prospectively validated in a high-risk population.

A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis.

OBJECTIVE: To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis. METHODS: Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens. RESULTS: The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 micrograms/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 micrograms/mL and required dose adjustment, a statistically significant difference (P < .001). Pharmacy costs averaged $16.12 +/- 5.68 for the study group and $41.75 +/- 17.41 for the control group, also a significant difference (P < .001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the study group and 28.06 +/- 8.77 minutes for the control group (P < .001). CONCLUSION: In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience.

OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk.

Depot medroxyprogesterone acetate contraception in women with medical problems.

Since few clinical trials of contraceptive agents are conducted on women with medical problems, use of these agents in these populations is often based more upon theoretical considerations than clinical data. Clinicians must distinguish the risk of estrogen in the combined oral contraceptive from the risk of the progestin-only contraceptive methods. This review compares the risks of pregnancy with the risks of contraceptive methods for patients with chronic hypertension, cardiac disease, thrombotic disorders, diabetes, epilepsy, lupus erythematosus and other medical disorders. For women with certain medical problems, estrogen, but not progestogen, may be contraindicated. For these women, a long-acting progestogen, such as depot medroxyprogesterone acetate (DMPA), may offer distinct advantages.

PIP: The contraceptive implant depot medroxyprogesterone acetate (DMPA) may offer advantages to women with medical problems which contraindicate the use of estrogen. In such women, the risks of pregnancy must be weighted against the risk posed by a contraceptive method. While young women with well-controlled hypertension can use DMPA or the combined oral contraceptive, patients with uncontrolled hypertension or other risk factors may be better managed with DMPA. DMPA is also an appropriate choice for many women with cardiac disorders which can be associated with an extremely high risk of adverse pregnancy outcomes. Because it is not associated with increased thrombotic risk, DMPA is also safe in women over 35 years old who smoke. The contraceptive is likewise indicated in women with a history of thromboembolic disease (despite package labeling which was based on trials of high doses of DMPA as a cancer treatment). DMPA also is safe in women with sickle cell disease and actually has been shown to reduce the incidence of sickle cell crisis. Evidence also suggests that DMPA injections in anticoagulated women do not increase the incidence of hematoma formation. DMPA will not protect women with underlying predisposing causes of thrombosis from experiencing a thrombotic event. Whereas the contraceptive efficacy of hormonal contraception may be reduced in epileptic women using hepatic enzyme induction agents, DMPA has been reported to reduce seizure frequency with few contraceptive failures in such women. In diabetic women with peripheral vascular disease and in women with systemic lupus erythematosus, DMPA, unlike contraceptives with estrogen, avoids the enhanced risk of thrombosis. Because the best pregnancy outcome in women with medical problems occurs when the pregnancy is planned, such women should use the most effective contraceptive methods available to them.

Prediction of preterm birth in nulliparous patients.

OBJECTIVE: Our goal was to determine whether the mammary stimulation test combined with a risk scoring system and cervical examination at 26 to 28 weeks' gestation could effectively identify private nulliparous patients at risk for spontaneous preterm birth. STUDY DESIGN: The mammary stimulation test was performed by 267 nulliparous patients with singleton gestations at 26 to 28 weeks. Risk scores were determined by the method of Creasy et al. and cervical examinations were performed at the first prenatal visit and at 26 to 28 weeks. Summary predictive values were calculated for each test, and a stepwise discriminate analysis was performed. RESULTS: Spontaneous preterm birth occurred at < 37 weeks in 26 of 265 (9.8%) patients. The following variables were independently associated with spontaneous preterm birth: positive result of mammary stimulation test, risk score > or = 10, soft cervix at 26 to 28 weeks, bacteriuria, and current smoking. The best discriminate model included positive result of mammary stimulation test, soft cervix, bacteriuria, current smoking, and prior spontaneous abortion(s). This model identified 19 patients as being at risk for spontaneous preterm birth with sensitivity of 35%, specificity of 96%, and positive predictive value of 47%. CONCLUSION: Combining the mammary stimulation test with a cervical examination at 26 to 28 weeks' gestation and routinely obtained prenatal data correctly identified 35% of spontaneous preterm births in nulliparous patients with a positive predictive value of 47%. Prospective validation of this model is warranted.

Mammary stimulation test predicts preterm birth in nulliparous women.

OBJECTIVE: This prospective clinical trial was designed to assess the ability of the mammary stimulation test to predict preterm birth in a private nulliparous population. STUDY DESIGN: The mammary stimulation test was performed between 26 and 28 weeks' gestation by 267 nulliparous women with singleton pregnancies. Test results were blinded to both patient and referring physician. Pregnancy outcome data were collected from the perinatal database and medical records. RESULTS: The mammary stimulation test was positive in 45 of 266 (17%) patients. Delivery occurred at < 37 weeks in 27 patients (10.2%) and at < 34 weeks in five (1.9%). The mammary stimulation test demonstrated a sensitivity of 37%, a specificity of 84%, a positive predictive value of 20%, and a negative predictive value of 92% for delivery at < 37 weeks' gestation. For delivery at < 34 weeks' gestation the mammary stimulation test had a sensitivity of 60%, a specificity of 82%, a positive predictive value of 6%, and a negative predictive value 99%. The odds ratio for delivery at < 37 weeks was 3.0 (95% confidence interval 1.3, 7.1), and for delivery at < 34 weeks the odds ratio was 7.0 (95% confidence interval 1.1, 43.0). One third of preterm deliveries were secondary to idiopathic preterm labor, and the mammary stimulation test was positive in 77.8% (seven of nine) of these pregnancies. Patients with a positive test were more likely to require observation in labor and delivery for preterm uterine contractions (34% vs 4.3%, p < 0.01), and they were more likely to demonstrate change at cervical examination (14% vs 2%, p < 0.01). CONCLUSION: In this population traditionally considered to be at low risk for preterm birth a positive mammary stimulation test was useful in identifying patients at risk for preterm uterine activity and preterm birth. Equally important was the identification of women who were at low risk for preterm birth.

Simultaneous analysis of inulin and 15N2-urea kinetics in humans.

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 +/- 0.009 L/kg (+/- SD) for inulin and of 0.670 +/- 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 +/- 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 +/- 0.40 L/min).

Pharmacokinetics of prednisolone transfer to breast milk.

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

The risk and efficacy of chorionic villus sampling in multiple gestations.

Chorionic villus sampling (CVS) in the first trimester of pregnancy provides a safe and effective method for the early prenatal diagnosis of cytogenetic abnormalities in multiple gestations. In this multicentre study involving 126 twin and 2 triplet gestations primarily at risk because of advanced maternal age, the overall success rate of obtaining an adequate villus sample from each fetus was 99.2 per cent. For women of advanced maternal age, the rate of combined losses of chromosomally normal fetuses due to spontaneous abortion, stillbirths, and neonatal deaths was 5.0 per cent, compared with a 4.0 per cent total loss rate following CVS in singleton pregnancies derived from the same population (Rhoads et al., 1989). There was a 100 per cent success rate in obtaining a cytogenetic analysis; a cytogenetic abnormality was present in five of the multiple gestations (3.9 per cent) and involved seven fetuses (2.7 per cent). There were no diagnostic errors and no cases of normal cytogenetic diagnosis followed by the birth of a cytogenetically abnormal newborn. Based on cases of XX/XY admixture, cell contamination derived either from maternal decidua or the other twin occurred in 6 of 256 samples (2.3 per cent), giving an overall estimate of the frequency of cell contamination of 4.6 per cent; these cases did not present a diagnostic problem. However, there were two cases (0.8 per cent) in which the fetal sex was incorrect, due either to complete maternal cell contamination or to the possibility that in error one twin was sampled twice.

Fetal reduction: is this the appropriate answer to multiple gestation?

PIP: Fetal reduction techniques, experiences at Northwestern University of Evanston, Illinois, USA, and ethical issues are discussed. The use of fetal reduction pertains to higher order multiple pregnancies due to successful fertility treatments. The risk associated with multifetal pregnancy is preterm delivery i.e., 29-31 weeks for quadruplets. In addition, survivors often have a high risk of congenital abnormalities and complications related to prematurity. 1978 marked the 1st time selective termination was possible. Other terms include "selective" birth, reduction, feticide, abortion, and multiple pregnancy reduction. The procedure takes place in the 1st or 2nd trimester, and procedures are similar to an elective abortion but with different techniques. Although there are many techniques, the preferred one is transabdominal cardiac puncture and injection of potassium chloride. A highly skilled ultrasonographer is essential for a successful technique. The complexity of the technique is one where the physician from a 2-dimensional screen must envision a 3-dimensional picture of the uterus and contents. Accurate needle placement is important. The reports from 7 clinical trials using the intracardiac potassium chloride technique are presented. The Northwestern experience includes 25 reductions between 1987-91 using fentanyl and midazolidocaine analgesia and general anesthesia with 1% lidocaine. Gestational age ranged from 9 to 13 weeks. There was total loss in 2 cases and deliveries in 8 cases including neonatal death of a very preterm set of twins. At or = 37 weeks, there were 11 pregnancies. 11 patients were or = 35 years, and 4 of the 20 30 years. In 33% of cases, only 1 pregnancy was left, which is dissimilar to other studies. Many difficulties may be faced with a complete pregnancy loss where there is a lack of support for the decision for fetal reduction. 2 concerns are mentioned in the ethical debate: the adequacy of counseling and the criteria for determining how many reductions per pregnancy. Difficulties arise in physician counseling when patients are unable to assimilate complex and detailed information, and physicians may not accurately convey information. Institutions may bias patient counseling. When an abnormality exists, the decision is easy; but with multiple normal development, the recommendation is twins. The Northwestern recommendation involves patient and family decisions and joint discussion of risk. The likelihood of severely premature delivery and maternal morbidity should also be considered, as well as the medical cost incurred with delivery and care of preterm multiple infants i.e., 1.2 million dollars for delivery of quads at 27 weeks. Science should be directed to reducing multiple pregnancies by refining technique and using fetal reduction as an interim technique. Fetal reduction is not appropriate for all multiple pregnancies.^ieng

An elevated maternal serum alpha-fetoprotein leading to the diagnosis of an immature teratoma.

A case report is presented of a woman with a maternal serum alpha-fetoprotein 17.46 multiples of the median (MOM), who was found to have an ovarian immature teratoma. It is suggested that patients who present with a maternal serum alpha-fetoprotein value greater than 9 multiples of the median receive a more comprehensive evaluation remembering that the alpha-fetoprotein in the adult can be a tumor marker.

Physiological basis of multicompartmental models of drug distribution.

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Asthma and pregnancy: responsibility of physicians and patients.

The successful management of asthma during pregnancy requires a cooperative approach between the obstetrician, the physician managing the asthma, and the patient. This is emphasized by a case report describing a patient with uncontrolled asthma subsequently managed with appropriate medical and obstetrical care. Concern for maternal and fetal health and reassurance of patients are primary concerns. Guidelines for physicians and patients are outlined as are the safety of drugs and therapy in pregnant patients. Physicians must have knowledge of appropriate use of medications during pregnancy.

Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women.

Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 +/- 0.3 gm/dl (+/- SD) in pregnant subjects, compared with 4.4 +/- 0.3 gm/dl in control subjects (p less than 1 x 10(-6], and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 +/- 1.0) than in nonpregnant (N = 3.3 +/- 0.4) subjects, but binding affinity (ka) averaged only 227 +/- 69 (mol/L)-1 in pregnant subjects, compared with 303 +/- 44 (mol/L)-1 in control subjects (F2,17 = 4.26; p = 0.032). At a theophylline plasma concentration of 10 micrograms/ml, the combined effects of hypoalbuminemia and lowered ka would reduce theophylline binding to 31% +/- 3% in pregnant women, compared to 39% +/- 3% in nonpregnant control subjects (p less than 1 x 10(-5]. Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy-associated decrease in theophylline binding.

Splanchnic tissues are a major part of the rapid distribution spaces of inulin, urea and theophylline.

Distribution of kinetics of inulin, [14C]urea and theophylline were studied in five anesthetized dogs after splenectomy and gastrointestinal resection. Distribution was modeled with three-compartment mammillary systems in which the central compartment corresponds to intravascular space and the two peripheral compartments have different rates of transcapillary exchange. Compared with results in intact dogs, the surgical procedure removed between 41 and 55% of the rapidly equilibrating tissues and reduced the permeability coefficient-surface area products for the rapidly equilibrating inulin and urea compartments proportionately. This is consistent with the concept that splanchnic organs equilibrate rapidly with inulin and urea because they are supplied by fenestrated and discontinuous capillaries that are prominent in the splanchnic vascular bed. However, splanchnic organs probably do not contain all rapidly equilibrating tissues, and somatic tissues may contribute as much as 36 and 22%, respectively, of the rapidly equilibrating inulin and urea compartments. Cardiac output averaged 2.87 +/- 0.86 liters/min and was similar to the sum of compartmental blood flows estimated from the intercompartmental clearances of urea and inulin (2.74 +/- 0.96 liters/min) and to the sum of theophylline intercompartmental clearances (2.62 +/- 0.74 liters/min). Theophylline intercompartmental clearance to each peripheral compartment was similar to estimated compartmental blood flow.